Protein and peptide drugs hold great promise as therapeutic agents. However, many are degraded by proteolytic enzymes, can be rapidly cleared by the kidneys, generate neutralizing antibodies and have a short circulating half-life. Pegylation, the process by which polyethylene glycol chains are attached to protein and peptide drugs, can overcome these and other shortcomings. By increasing the molecular mass of proteins and peptides and shielding them from proteolytic enzymes, pegylation improves pharmacokinetics. This article will review how PEGylation can result in drugs that are often more effective and safer, and which show improved patient convenience and compliance.

Effect of pegylation on pharmaceuticals

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22759

Diagnosis, management, and treatment of hepatitis C: An update

Hepatitis C virus (HCV) infects an estimated 170 million persons worldwide and thus represents a viral pandemic, one that is five times as widespread as infection with the human immunodeficiency virus type 1 (HIV-1). The institution of blood-screening measures in developed countries has decreased the risk of transfusion-associated hepatitis to a negligible level, but new cases continue to occur mainly as a result of injection-drug use and, to a lesser degree, through other means of percutaneous or mucous-membrane exposure. Progression to chronic disease occurs in the majority of HCV-infected persons, and infection with the virus has become the main indication . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200107053450107?listPDF=true

Hepatitis C Virus Infection

BACKGROUND:
Treatment with pegylated interferon (peginterferon) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE:
To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or standard dose of ribavirin. DESIGN:
Randomized, double-blind trial. SETTING:
99 international centers. PATIENTS: 1311 patients with chronic hepatitis C. PATIENTS:
1311 patients with chronic hepatitis C. INTERVENTION:
Peginterferon-?2a, 180 ?/wk, for 24 or 48 weeks plus a low-dose (800 mg/d) or standard weight-based dose (1000 or 1200 mg/d) of ribavirin. Measurement: Sustained virologic response: undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up. RESULTS:
Overall and in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks and standard-dose ribavirin was statistically superior to low-dose ribavirin. In patients with HCV genotype 1, absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2% (95% CI, 3.6% to 18.9%) and 11.9% (CI, 4.7% to 18.9%), respectively, between standard- and low-dose ribavirin. Sustained virologic response rates for peginterferon-alpha2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different. CONCLUSION:
Treatment with peginterferon-?2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.

Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose.

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and a potential cause of substantial morbidity and mortality in the future. The complexity and uncertainty related to the geographic distribution of HCV infection and chronic hepatitis C, determination of its associated risk factors, and evaluation of cofactors that accelerate its progression, underscore the difficulties in global prevention and control of HCV. Because there is no vaccine and no post-exposure prophylaxis for HCV, the focus of primary prevention efforts should be safer blood supply in the developing world, safe injection practices in health care and other settings, and decreasing the number of people who initiate injection drug use.

https://courses.washington.edu/conj504/readings/alter_reading3.pdf

Global epidemiology of hepatitis C virus infection

Background Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. Methods A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 μg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks. Results A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) th...

/pdf/peginterferon-alfa-2a-plus-ribavirin-for-chronic-hepatitis-c-lnfdfx9cd4.pdf

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

Pegylated (40kDa) interferon alfa-2a (PEGASYS®) in combination with ribavirin: Efficacy and safety results from a phase III, randomized, actively-controlled, multicenter study

7031 Background: LEN promotes erythropoiesis in a subset of lower risk MDS pts who fail EPO treatment (tx) [N Eng J Med 2005;352:549]. We reported that LEN acts to relieve suppression of the EPO-R signal in non-del(5q) MDS progenitors. We hypothesized that erythroid response (HI-E) to LEN is influenced by endogenous EPO level and can be augmented by combined tx (CT) with EPO in pts with low serum EPO (sEPO) concentration. To evaluate the potential benefit of CT, the effect of sEPO level, and the effects of LEN pharmacokinetics (PK) on cytopenias, we performed a two-stage PK and efficacy study. Methods: Eligible pts had transfusion-dependent (TD), Low/Int-1 IPSS MDS who failed prior treatment with EPO. In the 1st stage pts received LEN monotherapy (MT) at 10mg/d [n=25] or 15mg/d [n=15]. Single dose [n=12] and steady state [n=24] PK were evaluated on days -7 and +14 at the 10mg LEN dose. After 16 wks of MT, erythroid non-responders (NR) and minor (MiE) responders (IWG 2000) were offered CT with epoetin alph...

Jian Yu

Papers

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.

Pegylated (40kDa) interferon alfa-2a (PEGASYS®) in combination with ribavirin: Efficacy and safety results from a phase III, randomized, actively-controlled, multicenter study

Erythroid response to lenalidomide (LEN) + recombinant erythropoietin (EPO) and endogenous serum EPO concentration in MDS cytokine-failures