Drug information

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Other Names
PegIntron (brand product for the treatment of chronic hepatitis C [discontinued]), Sylatron (brand product for the treatment of melanoma [discontinued]), PEG-interferon alfa 2b (HIV), pegIFN alfa-2b (HIV), pegylated-interferon alfa 2b (HIV)
Drug Class
Immune Modulators
Registry Number
215647-85-1 (CAS)
Chemical Name

Monocarboxyinterferon alfa-2b, diesters with polyethylene glycol monomethyl ether

Chemical Class
Recombinant interferon
Organization
Merck Sharp & Dohme Corp.
Phase of Development

Peginterferon alfa-2b is in Phase 3 development for HIV treatment.

Chemical Image: (Click to enlarge)

peginterferon alfa-2b

(Compound details obtained from PubChem,1 WHO Drug Information,2 PegIntron Full Prescribing Information,3 and ClinicalTrials.gov4,5)

 

Pharmacology

Pharmacology

Mechanism of Action

Immune modulator. Peginterferon alfa-2b is recombinant alfa-2b interferon covalently linked with a 12 kD linear polyethylene glycol (PEG) chain. Its activity in vivo stems from the interferon alfa-2b component of the drug.3,6 Peginterferon alfa-2b was previously FDA-approved under the brand name PegIntron for the treatment of chronic HCV infection and under the brand name Sylatron for the treatment of melanoma; both products are no longer marketed in the United States.3,7-10

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 result in activation of 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.3,11-15

Of note, although peginterferon alfa-2b has been 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 T cells, and HIV disease progression.11,13,14,16-18

Half-life (T½)

In participants with chronic hepatitis C, the mean elimination half-life of peginterferon alfa-2b is approximately 40 hours (range 22 to 60 hours).3

Metabolism/Elimination

Thirty percent of peginterferon alfa-2b is cleared renally. The remainder of peginterferon alfa-2b is hepatically catabolized and degraded after it interacts with interferon receptors.3,19

Select Clinical Trials

Select Clinical Trials

Study Identifier: NCT01295515

Sponsor: National Cancer Institute (NCI)
Phase: 1/2
Status: This study has been completed.
Study Purpose: The purpose of this pilot study was to evaluate the effect of peginterferon alfa-2b on HIV residual viremia when peginterferon alfa-2b was used as an additional drug in participants with viral suppression on ART.
Study Population:

  • Participants were adults with HIV who were receiving ART.
  • Participants had cell-associated HIV RNA ≥5 copies/million PBMCs, HIV RNA <50 copies/mL for at least 12 months prior to screening, and CD4 counts ≥300 cells/mm3.16

Study Identifier: NCT01935089

Sponsor: The Wistar Institute
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this pilot study was to determine if treatment with peginterferon alfa-2b could reduce latent HIV reservoirs in participants with viral suppression on ART.
Study Population:

  • Participants were adults with HIV who were receiving ART and who had been on ART for more than 1 year.
  • Participants had HIV RNA <50 copies/mL at screening and for at least 1 year prior to screening and CD4 counts ≥450 cells/mm3 at screening.17,20

Selected Study Results: Results presented at CROI 2017 and published in AIDS Research and Human Retroviruses (2021) demonstrated that 20 weeks of treatment with peginterferon alfa-2b plus ART (with a 4-week analytical treatment interruption) led to a reduction in measures of HIV persistence and latent reservoir size. Specifically, there was a trend toward a decrease in integrated HIV DNA in circulating CD4 cells. In gut-associated lymphoid tissue (GALT) there was a significant reduction in the number of HIV RNA-positive cells.20,21


Study Identifiers: BEAT-HIV study; NCT02227277

Sponsor: The Wistar Institute
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this study was to determine if treatment with peginterferon alfa-2b could reduce latent HIV reservoirs in participants who were virally suppressed on ART.
Study Population:

  • Participants were adults with HIV who were receiving ART and who had been on ART for at least 1 year.
  • Participants had HIV RNA <50 copies/mL at screening and for at least 12 months prior to screening and CD4 counts >450 cells/mm3 at screening.22,23

Selected Study Results: Results presented at CROI 2019 found that both peginterferon alfa-2b plus an analytical treatment interruption of ART and peginterferon alfa-2b plus ART had no substantial effect on latent HIV reservoir size, as measured by a change in integrated HIV DNA during 20 weeks of treatment. However, treatment with peginterferon alfa-2b reduced other measurements of HIV persistence (inducible HIV p24 levels).23


Study Identifiers: ANRS 112 INTERPRIM trial; NCT00196638

Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Phase: 2/3
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate the ability of three different treatment strategies in reducing HIV RNA in participants who had acute primary HIV infection.
Study Population:

  • Participants were treatment-naive adults with HIV.
  • Participants had ongoing primary HIV-1, as determined by detectable plasma HIV-RNA and a negative or incomplete Western blot.24,25

Selected Study Results: Results published in the journal AIDS (2012) showed that fixed-cycles of ART treatment interruption with and without peginterferon alfa-2b had no effect on viral load levels when compared to ART alone.25


Study Identifiers: ANRS 105 INTERVAC trial; NCT00125814

Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Phase: 3
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate whether peginterferon alfa-2b administered during analytical treatment interruptions of ART could postpone the need for resumption of ART.
Study Population:

  • Participants were adults with HIV who had been receiving the same ART regimen for at least 6 months.
  • Participants had HIV RNA <400 copies/mL for at least 6 months. Participants had CD4 counts >350 cells/mm3 and nadir CD4 counts ≥100 cells/mm3.4,26

Selected Study Results: Results published in the journal AIDS (2011) demonstrated that peginterferon alfa-2b given during analytical treatment interruptions of ART is not beneficial in postponing the need for resuming ART.26


Other HIV treatment studies that involve peginterferon alfa-2b have been completed, including:

  • NCT00035360: A Phase 3 trial that evaluated the use of peginterferon alfa-2b administered in combination with optimized ART in heavily treatment-experienced adults.5
  • BEAT-2 (NCT03588715): A Phase 1 trial that evaluated the safety, tolerability, and antiviral activity of peginterferon alfa-2b in combination with two broadly neutralizing antibodies (3BNC117 and 10-1074) in individuals with HIV who underwent an analytical treatment interruption of ART.18 Results are available from CROI 2023.

Adverse Events

Adverse Events

NCT01935089

In this Phase 2 pilot study, 20 virologically suppressed participants with HIV on ART were enrolled to receive a 20-week course of weekly peginterferon alfa-2b. One participant experienced Grade 2 depression, and seven participants reported Grade 3 or higher neutropenia, which was considered a serious adverse event (SAE). Three participants discontinued treatment with peginterferon alfa-2b — two discontinuations were due to Grade 4 neutropenia and one discontinuation was due to depression. No unexpected SAEs were reported.17,20

BEAT-HIV study (NCT02227277)

In this Phase 2 trial, participants were randomized to peginterferon alfa-2b plus treatment interruption (n = 18), peginterferon alfa-2b plus ART (n = 18), or ART only (n= 18). Adverse events occurred in 72.2% of participants in the peginterferon alfa-2b plus treatment interruption arm, 61.1% of participants in the peginterferon alfa-2b plus ART arm, and 55.6% of participants in the ART only arm. In each of the peginterferon alfa-2b treatment arms, two participants had a Grade 3 or 4 AE that was treatment related.22,23

ANRS 112 INTERPRIM trial (NCT00196638)

In this Phase 2/3 trial involving 89 participants with acute primary HIV infection, the most common AEs overall were gastrointestinal events. AEs (asthenia, influenza-like syndrome, neutropenia, and anemia) occurred more frequently with peginterferon alfa-2b administration than without peginterferon alfa-2b administration; however, most of these AEs were not severe. Thirteen SAEs (mainly gastrointestinal, neuropsychiatric, and laboratory disorders) occurred: two in the continuous ART group, one in the ART with treatment interruption group, and 10 in the ART with treatment interruption plus peginterferon alfa-2b group. All neuropsychiatric SAEs occurred in participants who received peginterferon alfa-2b. These SAEs included suicide attempts, depression, and generalized epilepsy. Lipodystrophy was uncommon, and few HIV-related events occurred in the study. In participants who interrupted ART, no acute viral symptoms occurred.25

ANRS 105 INTERVAC trial (NCT00125814)

In this Phase 3 trial, 168 total participants were randomized to either treatment interruption of ART alone or treatment interruption of ART with peginterferon alfa-2b. One participant in the treatment interruption only group and six participants in the treatment interruption with peginterferon alfa-2b group withdrew from the study between Weeks 0 and 48. Fourteen SAEs were reported, with five occurring in the treatment interruption only group and nine occurring in the group undergoing treatment interruption with peginterferon alfa-2b. Peginterferon alfa-2b was not related to any of the SAEs. In the group receiving peginterferon alfa-2b, Grade 3 neutropenia occurred in two participants and Grade 2 hypertriglyceridemia occurred in one participant. Two HIV-related events occurred during the treatment interruption period.26

Drug Interactions

Drug Interactions

Peginterferon alfa-2b was an FDA-approved treatment for chronic hepatitis C and melanoma, and its interactions with specific drugs have been previously described. Peginterferon alfa-2b is an inhibitor of CYP1A2 and CYP2D6; therefore, peginterferon alfa-2b should be used cautiously with drugs that have a narrow therapeutic range and that are metabolized by CYP1A2 or CYP2D6.3,7
 

References

References

  1. National Center for Biotechnology Information. Substance record for SID 135317436, peginterferon alfa-2b , Source: ChemIDplus. Accessed August 23, 2023
  2. World Health Organization (WHO). WHO drug information. 2000;14(4). Accessed August 23, 2023
  3. Merck Sharp & Dohme Corp. PegIntron: full prescribing information, September 2021 [archived drug label] DailyMed. Accessed August 23, 2023
  4. French National Agency for Research on AIDS and Viral Hepatitis. Multi-center trial to evaluate the efficacy and safety of structured treatment interruptions with or without pegylated interferon alpha for HIV-infected patients after prolonged viral suppression (ANRS 105 INTERVAC). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 1, 2005. NLM Identifier: NCT00125814. Accessed August 23, 2023
  5. Merck Sharp & Dohme Corp. Phase 3 study of PEG-Intron in heavily treatment-experienced, HIV-infected patients. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 2, 2002. NLM Identifier: NCT00035360. Accessed August 23, 2023
  6. Noureddin M, Ghany MG. Pharmacokinetics and pharmacodynamics of peginterferon and ribavirin: implications for clinical efficacy in treatment of chronic hepatitis C. Gastroenterol Clin North Am. 2010;39(3):649-658. doi:10.1016/j.gtc.2010.08.008. Accessed August 23, 2023
  7. Merck Sharp & Dohme Corp. Sylatron: full prescribing information, September 2021 [archived drug label]. DailyMed. Accessed August 23, 2023
  8. U.S. Food and Drug Administration (FDA) website. Dear health care professional letter, dated March 2015. Merck voluntarily discontinuing all doses of PEGINTRON® (peginterferon alfa-2b) REDIPEN® single-use pre-filled pen. Accessed August 23, 2023
  9. U.S. Food and Drug Administration (FDA) website. Dear pharmaceutical purchaser letter, dated August 2015. Merck voluntarily discontinuing all doses of PEGINTRON® (peginterferon alfa-2b) vials. Accessed August 23, 2023
  10. U.S. Food and Drug Administration (FDA) website. FDA drug shortages: current and resolved drug shortages and discontinuations reported to FDA. Peginterferon alfa-2b (Sylatron) (Discontinuation). Accessed August 23, 2023
  11. 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 August 23, 2023
  12. 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 August 23, 2023
  13. 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 August 23, 2023
  14. 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 Immunology. 2014;3(2):e10. doi:10.1038/cti.2014.1. Accessed August 23, 2023
  15. 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 August 23, 2023
  16. National Institute of Allergy and Infectious Diseases (NIAID). Effect of interferon alpha 2b intensification on HIV-1 residual viremia in individuals suppressed on antiretroviral therapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 11, 2011. NLM Identifier: NCT01295515. Accessed August 23, 2023
  17. The Wistar Institute. Pilot study: single arm, multi-site, open-label study to assess the effectiveness of peg-IFN-a2b in decreasing the levels of cell-associated integrated viral DNA in HIV chronic infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 27, 2013. NLM Identifier: NCT01935089. Accessed August 23, 2023
  18. Luis Montaner. Pilot study on innate activation and viral control in HIV-infected adults undergoing an analytical treatment interruption after administration of pegylated interferon alpha 2b with broadly HIV-1 neutralizing antibodies (3BNC117, 10-1074). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 17, 20185. NLM Identifier: NCT03588715. Accessed August 23, 2023
  19. Zeuzem S. Do differences in pegylation of interferon alfa matter? Gastroenterology. 2010;138(1):34-36. Accessed August 23, 2023
  20. Papasavvas E, Azzoni L, Pagliuzza A, et al. Safety, immune, and antiviral effects of pegylated interferon alpha 2b administration in antiretroviral therapy-suppressed individuals: results of pilot clinical trial. AIDS Res Hum Retroviruses. 2021;37(6):433-443. doi:10.1089/AID.2020.0243. Accessed August 23, 2023
  21. Azzoni L, Papasavvas E, Chomont N, et al. Pegylated IFNα-2b decreases latent HIV measures in ART-suppressed subjects. Presented at: Conference on Retroviruses and Opportunistic Infections (CROI). February 13-16, 2017; Seattle, WA. Poster 326. Accessed August 23, 2023
  22. The Wistar Institute. Towards eradication: reducing proviral HIV DNA with interferon-a immunotherapy. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 25, 2014. NLM Identifier: NCT02227277. Accessed August 23, 2023
  23. Azzoni L. Interferon-α2b reduces inducible CD4-associated HIV in ART-suppressed individuals. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 4-7, 2019; Seattle, WA. Accessed August 23, 2023
  24. French National Agency for Research on AIDS and Viral Hepatitis. Multicentric trial comparing three therapeutical strategies in patients with acute primary HIV infection. ANRS 112 INTERPRIM. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 12, 2005. NLM Identifier: NCT00196638. Accessed August 23, 2023
  25. Goujard C, Emilie D, Roussillon C, et al. Continuous versus intermittent treatment strategies during primary HIV-1 infection: the randomized ANRS INTERPRIM Trial. AIDS. 2012;26(15):1895. doi:10.1097/QAD.0b013e32835844d9. Accessed August 23, 2023
  26. Boué F, Reynes J, Rouzioux C, et al. Alpha interferon administration during structured interruptions of combination antiretroviral therapy in patients with chronic HIV-1 infection: INTERVAC ANRS 105 trial. AIDS. 2011;25(1):115-118. Accessed August 23, 2023

 

 
 

Last Reviewed: August 23, 2023