Clinical trial NCT01295515: Interferon Alpha 2b Intensification in HIV-Positive Individuals on Antiretroviral Therapy
Official title: Effect of Interferon Alpha 2b Intensification on HIV-1 Residual Viremia in Individuals Suppressed on Antiretroviral Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: HIV Infection
Keywords: HIV
Replication
Antiretroviral
Interferon
Reservoirs
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2011-02-14
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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. 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, and can be made as an injectable drug known as PEGINTRON. 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).

Detailed description: As a result of combination antiretroviral therapy (ART), morbidity and mortality from acquired immunodeficiency syndrome has declined significantly in the past 15 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 (c. 50 copies/mL plasma), but HIV viremia persists even after prolonged suppressive therapy. The origin of this residual viremia is yet not clear, but data suggest that production from long lived HIV infected cells may contribute to viremia.

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 are 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. Kottilil and coworkers in the Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases (NIAID) have shown a decrease in HIV-1 ribonucleic acid (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. As such the effects of interferon on HIV viremia and cell associated HIV RNA are of growing interest.

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. As patients may have levels of HIV RNA that are lower than our limit of detection, we will also investigate levels of HIV nucleic acid species in cells as well. We will determine whether interferon alpha therapy will reduce residual viremia or cell associated HIV RNA in participants on suppressive ART, which will expand our understanding of persistent low-level viremia and the pathogenesis of HIV in infected individuals.

Eligibility 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 human immunodeficiency virus type 1 (HIV-1) infection by any licensed enzyme-linked immunosorbent assay (ELISA) test and confirmed by a Western Blot.
3. Receiving a Department of Health and Human Services (DHHS)-approved antiretroviral (ARV) regimen.
4. Level of cell-associated HIV ribonucleic acid (RNA) greater than or equal to 5 copies/million peripheral blood mononuclear cells (PBMC) done at screening visit 1.
5. HIV-1 RNA levels less than detectable by current commercial means (e.g., Roche Amplicor, b-deoxyribonycleic acid (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.
6. Cluster of differentiation 4 (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 interferon (INF) treatment. The Beck Depression Inventory score must be less than or equal to 13 at pre-entry visit.
12. No history of INF/pegylated interferon (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 Doctors 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 interleukin-2 (IL-2) or interleukin-12 (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.

Primary outcomes:
measure: Pre- and Post- Interferon Alpha on Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA)
timeFrame: week 4 (post) compared to week 0 (pre)
measure: Pre- and Post- Interferon Alpha on Human Immunodeficiency Virus Type 1 (HIV-1) Deoxyribonucleic Acid (DNA)
timeFrame: week 4 (post) compared to week 0 (pre)
Secondary outcomes:
measure: Fold Change in Ribonucleic Acid (RNA) and Deoxyribonucleic Acid (DNA) in Human Immunodeficiency Virus Type 1 (HIV-1) Genetic Variation in Individuals Undergoing Interferon Therapy
timeFrame: week 4 (post) and week 0 (pre)
measure: Pre-and Post- Plasma Human Immunodeficiency Virus (HIV) Ribonucleic Acid (RNA) in HIV-infected Individuals
timeFrame: week 4 (post) compared to week 0 (pre)
measure: Count of Participants With Serious and Non-serious Adverse Events Assessed by the Division of Acquired Immune Deficiency Syndrome (AIDS) Table for Grading Adult Adverse Events.
timeFrame: Date consent signed to date off study, approximately 66 months and 2 days.
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Frank Maldarelli, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3879-84. doi: 10.1073/pnas.0800050105. Epub 2008 Mar 10.
citation: Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007 Apr;3(4):e46. doi: 10.1371/journal.ppat.0030046.
citation: Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9403-8. doi: 10.1073/pnas.0903107106. Epub 2009 May 22.
citation: Somsouk M, Dunham RM, Cohen M, Albright R, Abdel-Mohsen M, Liegler T, Lifson J, Piatak M, Gorelick R, Huang Y, Wu Y, Hsue PY, Martin JN, Deeks SG, McCune JM, Hunt PW. The immunologic effects of mesalamine in treated HIV-infected individuals with incomplete CD4+ T cell recovery: a randomized crossover trial. PLoS One. 2014 Dec 29;9(12):e116306. doi: 10.1371/journal.pone.0116306. eCollection 2014.