Drugs

Peginterferon Alfa-2a (HIV)

Other Names: PEG-interferon alfa-2a (HIV), Pegasys (HIV), pegIFN alfa-2a (HIV), pegylated-interferon alfa 2a (HIV) Drug Class: Immune Modulators Registry Number: 198153-51-4 (CAS) Chemical Name: Interferon alphaA (human leukocyte), mono(N2,N6-dicarboxy-L-lysyl)deriv., diester with alpha-methyl-omega-hydroxypoly(oxy-1,2-ethanediyl) Chemical Class: Recombinant interferon Organization: Hoffman-La Roche Phase of Development: Peginterferon alfa-2a is in Phase II development for HIV treatment.

Chemical Image:

(Click to enlarge)
peginterferon alfa-2a

peginterferon alfa-2a

Molecular Weight: 348.3734

(Compound details obtained from ChemIDplus Advanced,1 NIAID Therapeutics Database,2 Pegasys Full Prescribing Information,3 and ClinicalTrials.gov4

Pharmacology


Mechanism of Action: Immune modulator. Peginterferon alfa-2a (brand name: Pegasys) is a recombinant alfa-2a interferon covalently linked to a single-branched polyethylene glycol (PEG) chain. Its activity in vivo stems from the recombinant human interferon alfa-2a component of the drug. Peginterferon alfa-2a is an FDA-approved drug indicated for the treatment of chronic HBV infection and chronic HCV infection.3

Naturally occurring human interferon alfa, of which there are 13 subtypes, is a cytokine that belongs to a family of type I interferons. Interferon alfa has various functions in both innate and adaptive immune responses to viral pathogens, acting on natural killer (NK) cells, B cells, T cells, dendritic cells (DCs), and phagocytic cells. Interferon alfa binds to the human type 1 interferon receptor and triggers intracellular signaling pathways (mainly the JAK-STAT pathway) that activate interferon-stimulated genes (ISGs). Through various mechanisms, such as activation of endoribonuclease production and hypermutation of retroviral RNA, certain ISGs can have a role in controlling HIV replication.3,5-9

Although interferon alfa-2a is being studied for its anti-HIV activity and ability to enhance eradication of HIV, the biological role of interferon alfa in chronic HIV infection has also been described as being detrimental, causing persistent immune activation, depletion of CD4 cells, and HIV disease progression.5,7,8

Half-life (T½): Following subcutaneous dosing in participants with chronic HCV, the mean terminal half-life of peginterferon alfa-2a was 160 hours.3

Metabolism/Elimination: The primary elimination route of peginterferon alfa-2a is hepatic metabolism.10


Select Clinical Trials


Study Identifiers: ACTG A5192; NCT00078442
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and antiviral activity of peginterferon alfa-2a monotherapy in participants with HIV who were not receiving ART.
Study Population:
  • Participants were adults with HIV who were either treatment-naive or treatment-experienced but off ART for at least 12 weeks before study entry. Participants were willing to defer initiation (or re-initiation) of ART until after completing the study.
  • Participants were HBV- and HCV-uninfected at study entry.
  • Participants had HIV RNA ≥5,000 copies/mL and CD4 counts ≥300 cells/mm3.11
Selected Study Results:
Study Identifier: NCT00594880
Sponsor: The Wistar Institute
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate the safety and antiviral activity of two different doses of peginterferon alfa-2a in participants with HIV who were virologically suppressed and on ART.
Study Population:
  • Participants were adults with HIV who were receiving ART and who were HBV- and HCV-uninfected at study entry.
  • Participants had HIV RNA <50 copies/mL, CD4 counts >450 cells/mm3, and had nadir CD4 counts of >200 cells/mm3.4,12
Selected Study Results:
Study Identifiers: ACTIVATE; NCT02471430
Sponsor: Massachusetts General Hospital
Phase: I/II
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate whether a combination regimen consisting of the histone deacetylase inhibitor (HDACi) panobinostat and peginterferon alfa-2a can reduce latent HIV reservoirs.
Study Population:
  • Participants are adults with HIV who have been receiving continuous ART for at least 24 months prior to screening and who have been receiving the same ART regimen for at least 12 weeks prior to screening.
  • Participants are HBV- and HCV-uninfected at study entry.
  • Participants have been virologically suppressed on ART, with HIV RNA <50 copies/mL, for at least 24 months prior to screening and have CD4 counts ≥400 cells/mm3.13


Adverse Events


ACTG A5192 (NCT00078442):
In this Phase II trial that enrolled 13 participants with HIV, two participants discontinued peginterferon alfa-2a for reasons that were unrelated to the study drug. The most common adverse events (AEs) that were related (or possibly related) to peginterferon alfa-2a treatment were Grade 1 or 2 absolute neutrophil count (ANC) decreases, which occurred in 11 out of 13 participants, and fatigue, which occurred in six out of 13 participants. One participant experienced Grade 2 treatment-related depression. Grade 3 treatment-related events included fatigue (which occurred in one participant) and decreased ANC (which occurred in two participants). One of these three participants was treated with a single dose of filgrastim, and all three participants completed the study at reduced peginterferon alfa-2a doses.11,14

NCT00594880:
During this Phase II study, 23 participants were assigned to receive peginterferon alfa-2a doses of either 180 mcg per week or 90 mcg per week. Three participants discontinued peginterferon alfa-2a because of moderate depression. One participant, who had Grade 3 neutropenia while still receiving ART, also discontinued the study. During the first 5 weeks of peginterferon alfa-2a treatment, an expected drop in median CD4 count was observed in study participants; however, the CD4 count levels remained stable throughout the remainder of the study, and no participants discontinued treatment because of a drop in CD4 count.12

Additional AEs that have been associated with the use of peginterferon alfa-2a are described in the FDA-approved Full Prescribing Information for Pegasys.


Drug Interactions


Peginterferon alfa-2a does not alter the pharmacokinetics of probe drugs that are known to be metabolized by the following CYP enzymes: CYP2C9, CYP2C19, CYP2D6, and CYP3A4. However, treatment with peginterferon alfa-2a has been associated with inhibition of CYP1A2.3

Peginterferon alfa-2a is an FDA-approved treatment for chronic HBV and chronic HCV, and its interactions with other drugs have been previously described. Cases of hepatic decompensation have been reported in individuals with cirrhotic chronic HCV/HIV coinfection who were receiving peginterferon alfa-2a and NRTIs.3

Concomitant use of zidovudine with peginterferon alfa-2a and ribavirin has been associated with severe neutropenia and severe anemia.3

Additional interactions between peginterferon alfa-2a and coadministered drugs are described in the FDA-approved Full Prescribing Information for Pegasys.


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Peginterferon Alfa-2a. https://chem.nlm.nih.gov/chemidplus/rn/198153-51-4. Accessed April 23, 2019.
  2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed April 23, 2019.
  3. Genentech, Inc. Pegasys: full prescribing information, June 26, 2018. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=de61685e-2b8c-4e22-84bb-869e13600440. Accessed April 23, 2019.
  4. The Wistar Institute. Antiviral activity of peg-IFN-alpha-2A in chronic HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 4, 2008. NLM Identifier: NCT00594880. https://www.clinicaltrials.gov/ct2/show/NCT00594880. Accessed April 23, 2019.
  5. Chang JJ, Altfeld M. Innate immune activation in primary HIV-1 infection. J Infect Dis. 2010;202(Suppl 2):S297-S301. doi:10.1086/655657
  6. Hubbard JJ, Greenwell-Wild T, Barrett L, et al. Host gene expression changes correlating with anti–HIV-1 effects in human subjects after treatment with peginterferon alfa-2a. J Infect Dis. 2012;205(9):1443-1447. doi:10.1093/infdis/jis211
  7. Sivro A, Su R-C, Plummer FA, Ball TB. Interferon responses in HIV infection: from protection to disease. AIDS Rev. 2014;16:43-51.
  8. Cha L, Berry CM, Nolan D, Castley A, Fernandez S, French MA. Interferon-alpha, immune activation and immune dysfunction in treated HIV infection. Clin Transl Immunol. 2014;3(2):e10. doi:10.1038/cti.2014.1
  9. Gibbert K, Schlaak J, Yang D, Dittmer U. IFN-α subtypes: distinct biological activities in anti-viral therapy. Br J Pharmacol. 2013;168(5):1048-1058. doi:10.1111/bph.12010
  10. van Leusen R, Adang R PR, de Vries RA, et al. Pegylated interferon alfa-2a (40 kD) and ribavirin in haemodialysis patients with chronic hepatitis C. Nephrol Dial Transpl. 2008;23(2):721-725.
  11. National Institute of Allergy and Infectious Diseases (NIAID). A Phase II open-label pilot trial of the antiretroviral activity, safety, and tolerability of pegylated interferon alfa-2a (40KD) [PegasysTM] in HIV-1 infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 25, 2004. NLM Identifier: NCT00078442. https://www.clinicaltrials.gov/ct2/show/NCT00078442. Accessed April 23, 2019.
  12. Azzoni L, Foulkes AS, Papasavvas E, et al. Pegylated interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis. 2013;207(2):213-222. doi:10.1093/infdis/jis663
  13. Massachusetts General Hospital. A Phase I-II pilot study to assess the safety and efficacy of combined administration with pegylated interferon-alpha2a and the histone deacetylase inhibitor (HDACi) panobinostat for reducing the residual reservoir of HIV-1 infected cells in cART-treated HIV-1 positive individuals. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on June 11, 2015. NLM Identifier: NCT02471430. https://www.clinicaltrials.gov/ct2/show/NCT02471430. Accessed April 23, 2019.
  14. Asmuth DM, Murphy RL, Rosenkranz SL, et al. Safety, tolerability and mechanisms of antiretroviral activity of peginterferon alfa-2a in HIV-1-mono-infected subjects: a Phase II clinical trial. J Infect Dis. 2010;201(11):1686–1696.


Last Reviewed: April 23, 2019