Drugs

Peginterferon Alfa-2b (HIV)

Other Names: PEG-interferon alfa 2b (HIV), PegIntron (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 III development for HIV treatment.

Chemical Image:

(Click to enlarge)
peginterferon alfa-2b

peginterferon alfa-2b

Molecular Weight: 118.1112

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

Pharmacology


Mechanism of Action: Immune modulator. Peginterferon alfa-2b (brand name: PegIntron) 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 is an FDA-approved drug indicated for the treatment of 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 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.3,7-11

Of note, although peginterferon alfa-2b 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 T cells, and HIV disease progression.7,9,10,12,13

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.3,14


Select Clinical Trials


Study Identifier: NCT01295515
Sponsor: National Cancer Institute (NCI)
Phase: I/II
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/mm3.12

Study Identifier: NCT01935089
Sponsor: The Wistar Institute
Phase: II
Status: This study has been completed.
Study Purpose: The purpose of this pilot study was to determine if treatment with peginterferon alfa-2b can reduce latent HIV reservoirs (as measured by cell-associated integrated HIV-1 DNA levels) 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.13,15,16
Selected Study Results:

Study Identifiers: BEAT-HIV study; NCT02227277
Sponsor: The Wistar Institute
Phase: II
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to determine if treatment with peginterferon alfa-2b can reduce latent HIV reservoirs (as measured by integrated HIV-1 DNA levels) in participants who are virally suppressed on ART.
Study Population:
  • Participants are adults with HIV who are receiving ART and who have been on ART for at least 1 year.
  • Participants have HIV RNA <50 copies/mL at screening and for at least 12 months prior to screening and CD4 counts >450 cells/mm3 at screening.17

Study Identifiers: ANRS 112 INTERPRIM trial; NCT00196638
Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Phase: II/III
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 have acute primary HIV.
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.18,19
Selected Study Results:
Study Identifiers: ANRS 105 INTERVAC trial; NCT00125814
Sponsor: French National Agency for Research on AIDS and Viral Hepatitis
Phase: III
Status: This study has been completed.
Study Purpose: The purpose of this study was to evaluate whether interferon alfa-2b administered during treatment interruption 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/mm3.4,20 

Selected Study Results:

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

  • NCT00035360: A completed Phase III trial that evaluated the use of peginterferon alfa-2b administered in combination with optimized ART in heavily treatment-experienced adults.5
  • NCT03588715: A Phase I trial that will evaluate the safety, tolerability, and antiviral activity of peginterferon alfa-2b when it is used in combination with two broadly neutralizing antibodies (3BNC117 and 10-1074) in individuals with HIV who are undergoing a treatment interruption of ART.21


Adverse Events


NCT01935089:
In this Phase II pilot study evaluating a 20-week course of weekly peginterferon alfa-2b in virologically suppressed participants with HIV on ART, 20 participants were enrolled and 18 completed treatment. Among those who completed treatment, seven Grade 3 or 4 adverse events (AEs) were reported. Neutropenia was the most common adverse event (AE) and was considered a serious adverse event (SAEs) in six participants; all cases were managed with treatment and/or study drug termination. One participant withdrew from the study because of Grade 2 dysthymia. No unexpected AEs were reported.15,16

ANRS 112 INTERPRIM trial (NCT00196638):
In this Phase II/III 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.19

ANRS 105 INTERVAC trial (NCT00125814):
In this Phase III 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.20

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


Drug Interactions


Peginterferon alfa-2b is an FDA-approved treatment for chronic hepatitis C, 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

Individuals with HIV and cirrhotic chronic HCV who are receiving combination ART and alpha interferons with or without ribavirin may be at a higher risk for hepatic decompensation than patients who are not receiving ART. Use of peginterferon alfa-2b with ribavirin in combination with NRTIs requires monitoring for toxicities, including hepatic decompensation and anemia.3

In vitro, ribavirin has been shown to reduce the phosphorylation of lamivudine, stavudine, and zidovudine; however, in a study that used a combination of another pegylated interferon and ribavirin, no pharmacokinetic or pharmacodynamic interaction was seen between ribavirin and lamivudine, stavudine, or zidovudine.3

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

Additional interactions between peginterferon alfa-2b and coadministered drugs are described in the Full Prescribing Information for PegIntron.3


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Peginterferon Alfa-2b. https://chem.nlm.nih.gov/chemidplus/rn/215647-85-1. Accessed May 21, 2019.
  2. World Health Organization (WHO). WHO drug information. 2000;14(4). http://apps.who.int/medicinedocs/pdf/s2201e/s2201e.pdf. Accessed May 21, 2019.
  3. Merck Sharp & Dohme Corp. PegIntron - peginterferon alfa-2b: Full prescribing information. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b70816bb-913a-467f-acb8-67ef62cf8dac. Published February 2017. Accessed May 21, 2019.
  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. https://clinicaltrials.gov/ct2/show/NCT00125814. Accessed May 21, 2019.
  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. https://clinicaltrials.gov/ct2/show/NCT00035360. Accessed May 21, 2019.
  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
  7. 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
  8. 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
  9. Sivro A, Su R-C, Plummer FA, Ball TB. Interferon responses in HIV infection: from protection to disease. AIDS Rev. 2014;16:43-51.
  10. 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
  11. 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
  12. 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. https://clinicaltrials.gov/ct2/show/NCT01295515. Accessed May 21, 2019.
  13. 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. https://clinicaltrials.gov/ct2/show/NCT01935089. Accessed May 21, 2019.
  14. Zeuzem S. Do differences in pegylation of interferon alfa matter? Gastroenterology. 2010;138(1):34-36.
  15. Azzoni L, Papasavvas E, Lynn K, et al. A feasibility study of weight-based pegylated IFN-α2b immunotherapy to target persistent HIV-1 on ART. Presented at the: 8th International AIDS Society (IAS) Conference on HIV Pathogenesis, Treatment & Prevention. July 19-22, 2015; Vancouver, Canada. Poster TUPEB297. http://pag.ias2015.org/PAGMaterial/eposters/2852.pdf. Accessed May 21, 2019.
  16. Azzoni L, Papasavvas E, Chomont N, et al. Pegylated IFNa-2b decreases latent HIV measures in ART-suppressed subjects. Presented at the: 23rd Conference on Retroviruses and Opportunistic Infections (CROI). February 13-16, 2017; Seattle, WA. Poster 326. http://www.croiconference.org/sites/default/files/posters-2017/326_Azzoni.pdf. Accessed May 21, 2019.
  17. 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. https://clinicaltrials.gov/ct2/show/NCT02227277. Accessed May 21, 2019.
  18. 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. https://clinicaltrials.gov/ct2/show/NCT00196638. Accessed May 21, 2019.
  19. 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
  20. 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.
  21. 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. https://clinicaltrials.gov/ct2/show/NCT03588715. Accessed May 21, 2019.


Last Reviewed: May 21, 2019