Drug Database: Peginterferon Alfa-2a (HIV)

Pharmacology

Pharmacology

Mechanism of Action

Immune modulator. Peginterferon alfa-2a 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 FDA-approved under the brand name Pegasys 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.^5,7,8,10

Half-life (T_½)

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.¹¹

Select Clinical Trials

Select Clinical Trials

Study Identifiers: ACTG A5192; NCT00078442

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Phase: 2
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/mm³.¹²

Selected Study Results: Results published in the Journal of Infectious Diseases (2010) showed that monotherapy with peginterferon alfa-2a over 12 weeks led to significant reductions in participants’ viral load levels. Treatment-related side effects included depression, fatigue, and decreased neutrophils.¹³
Additional Published Material:

• J Infect Dis article, 2012: Host gene expression changes correlating with anti–HIV-1 effects in human subjects after treatment with peginterferon alfa-2a

Study Identifier: NCT00594880

Sponsor: The Wistar Institute
Phase: 2
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 nadir CD4 counts of >200 cells/mm³.^4,14

Selected Study Results: Results published in the Journal of Infectious Diseases (2013) showed that the administration of peginterferon alfa-2a (given at either of two doses) led to sustained viral control in 45% of participants after analytical treatment interruption of ART. The proportion of participants maintaining viral load control during ART treatment interruption was greater than what investigators had anticipated based on historical data.¹⁴

Study Identifiers: NCT02767193

Sponsor: Judit Pich Martínez
Phase: 2a
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the safety and virological effects of an intranodally administered dendritic cell-based therapeutic HIV vaccine in combination with peginterferon alfa-2a in participants with HIV who were virologically suppressed on ART.
Study Population:

• Participants were adults with HIV who had been receiving ART for at least 1 year.
• Participants had undetectable HIV RNA for at least 6 months prior to study enrollment, CD4 counts ≥450 cells/mm³, and nadir CD4 counts ≥350 cells/mm³.^15,16

Selected Study Results: Findings published in Frontiers in Immunology (2021) showed that the combination of an intranodally administered dendritic cell-based vaccine with peginterferon alfa-2a was safe, with only one Grade 3 or higher treatment-related adverse event (AE) reported. However, the combination treatment had minimal impact on the main viral outcome measure. All participants experienced viral rebound prior to completing a 12-week analytical treatment interruption of ART.¹⁶

Study Identifiers: ACTIVATE; NCT02471430

Sponsor: Massachusetts General Hospital
Phase: 1/2
Status: This study is ongoing, but not 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 the latent HIV reservoir.
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/mm³.¹⁰

Selected Study Results: Results published at CROI 2022 showed that although panobinostat reactivated latent HIV and interferon alfa-2a induced immune activation in participants with virological suppression on ART, the combination regimen was ineffective in reducing latent HIV reservoir size.¹⁷

Adverse Events

Adverse Events

ACTG A5192 (NCT00078442)

In this Phase 2 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 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.^12,13

NCT00594880

During this Phase 2 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.¹⁴

NCT02767193

In this Phase 2a study, 36 participants were randomized to one of four groups: vaccine (n = 10), vaccine plus peginterferon alfa-2a (n = 9), placebo (n = 9), or placebo plus peginterferon alfa-2a (n = 8). Overall, the study interventions were safe, and the majority of AEs that occurred were mild in severity. The most common AE related to the intranodally administered dendritic cell-based vaccine was inguinal lymphadenopathy, while the most common AE related to subcutaneously administered peginterferon alfa-2a was asthenia. One participant who received placebo plus peginterferon alfa-2a experienced mild rash, which was deemed an allergic reaction related to peginterferon alfa-2a. Another participant who received the vaccine plus peginterferon alfa-2a experienced a Grade 3/4 AE—reactivation of M. malmoense pneumonia during analytical treatment interruption—which may have been related to study interventions.¹⁶

Additional AEs known to be associated with peginterferon alfa-2a are described in the FDA-approved Full Prescribing Information for Pegasys.³

Drug Interactions

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 known interactions between peginterferon alfa-2a and coadministered drugs are described in the FDA-approved Full Prescribing Information for Pegasys.³

References

References

1. National Center for Biotechnology Information. PubChem substance record for SID 135347948, peginterferon alfa-2a , Source: ChemIDplus. Accessed November 19, 2023
2. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed November 19, 2023
3. Genentech, Inc. Pegasys: full prescribing information, November 8, 2019. DailyMed. Accessed November 19, 2023
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. Accessed November 19, 2023
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. Accessed November 19, 2023
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. Accessed November 19, 2023
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. Accessed November 19, 2023
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. Accessed November 19, 2023
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. Accessed November 19, 2023
10. 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. Accessed November 19, 2023
11. 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. Accessed November 19, 2023
12. 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. Accessed November 19, 2023
13. 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. Accessed November 19, 2023
14. 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. Accessed November 19, 2023
15. Judit Pich Martínez. Safety and immunogenicity of a vaccine dendritic cell-based pulsed with autologous heat-inactivated HIV in HIV-1 infected patients. Prospective, randomized, partially blinded study. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 22, 2016. NLM Identifier: NCT02767193. Accessed November 19, 2023
16. Leal L, Couto E, Sánchez-Palomino S, et al. Effect of intranodally administered dendritic cell-based HIV vaccine in combination with pegylated interferon α-2a on viral control following ART discontinuation: a Phase 2A randomized clinical trial. Front Immunol. 2021;12:767370. doi:10.3389/fimmu.2021.767370. Accessed November 19, 2023
17. Armani-Tourret M, Hartana CA, Rassadkina Y, et al. HIV-1 viral reservoir disruption with panobinostat and IFN-⍺. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI)); February 12-16, 2022; Virtual. Poster 357. Accessed November 19, 2023

Last Reviewed: November 19, 2023