Current Review and Update on Hepatitis C & HIV/HCV Coinfection


Treatment of HCV

Goals of Therapy

The primary therapeutic goal is to eradicate HCV infection and in the process to effectively use predictors of a sustained therapeutic response. Other goals are to decrease the infectious pool, to achieve histologic benefit, and ultimately to improve quality of life. With current therapies, there are still a sizable number of patients with chronic HCV who do not respond to interferon and ribavirin therapy. However, even in patients who fail to respond to antiviral therapy, pegylated interferon might improve liver histology, slow disease progression and reduce the risk of hepatocellular carcinoma. Interferon is known to have an anti-inflammatory and an anti-fibrotic effect and the histologic benefit is most impressive in virologic responders and less so in viral nonresponders.

What is sustained virologic response (SVR)?

The same measurements that are used to determine disease severity (ALT, HCV RNA, and histological appearance on liver biopsy) are also used to determine if a therapeutic response has been achieved. Treatment for HCV is generally 48 weeks, or perhaps 24 weeks. In HIV/HCV coinfected individuals, 48 weeks of treatment is likely going to be the standard of care. The percent of patients with undetectable virus (<100 copies/ml) when treatment is stopped is called the End-Of-Treatment (ETR) Response. The key evaluation of therapy is the SVR. The SVR is the percent of patients with <100 copies/ml 24 weeks after treatment is stopped. The reason the SVR is the more important evaluation of the success of therapy is because patients who achieve an SVR are more likely to retain undetectable viral loads for years. Several small studies show that well over 90% of patients who achieve an SVR still have undetectable HCV for as long as they have been followed so far which is as far as 11 years. Some patients who achieve only an ETR can experience a viral relapse before 6 months after stopping therapy. So, the primary goal of therapy is to achieve the SVR.

Factors that predict a successful therapeutic response

Unlike HIV, it may be possible to eradicate HCV and the optimal duration of therapy has become an important issue. Five independent characteristics have been associated with a sustained virological response: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or minimal portal fibrosis, female gender, and age less than 40. Recently, Poynard et al (2000) suggested that all HCV-infected individuals be treated for 24 weeks at which time HCV RNA should be determined by PCR. If HCV RNA is detectable, treatment can be stopped. If the PCR is negative and the patient has fewer than four favorable factors, treatment should be continued for an additional 24 weeks. Additional factors, such as medication adherence and dosing antiviral medication based upon an individuals’ weight, are discussed below.

How is HCV treated?

Initially, interferon monotherapy (three million units three times per week) was used for the treatment of HCV. In 1998, two multicenter randomized trials demonstrated that the combination of interferon alfa-2b plus ribavirin was more effective than interferon monotherapy in the treatment of previously untreated (naïve) patients with chronic hepatitis C. Recently, interferon has been conjugated to polyethylene glycol, which results in once a week dosing. Interferon monotherapy studies yielded sustained viral responses in 10-15% of patients. The 2 large multicenter randomized trials of interferon alfa-2b plus ribivarin showed improved sustained viral responses of 38%-41%. Initial study results of pegylated interferon plus ribavirin show about 54% sustained virologic responses with 48 weeks therapy. Virologic response varies by genotype and these results are discussed below.

At DDW (May 2001), Thomas Shaw-Stieffell (University of Rochester) discussed the pharmacology of interferon. Standard interferon alfa given 3 times a week has limitations. It is rapidly absorbed after an injection, is widely distributed throughout the body, and is rapidly cleared by the kidneys, leading to a short plasma half-life of around 6 hours. When it is administered three times weekly, serum interferon levels fluctuate with an undetectable level in between the days of administration.

HCV has a half-life of around 3 hours and with a daily production of approximately 12 billion virions. Therefore, the large swings in standard interferon alfa concentrations may lead to a lack of sustained pressure on the virus leading to viral persistance. Lack of sustained pressure may lead to genetic mutations that could confer resistance to the medications that are used to treat HCV leading to viral persistence. The concept of pegylated interferon addresses these concerns.

Being able to administer interferon less frequently with sustained concentration over time with very little peak to trough variation ought to provide more optimal therapy. This has led to the pegylation of interferon. Pegylated interferon is a process that attaches a polyethylene glycol (PEG) molecule to a compound (drug) to increase its circulating time in the body. The size of the PEG, its branched versus linear structure, and the permanent bond between the PEG and the interferon have resulted in a once-weekly medication that has sustained absorption and reduced clearance, which allows the interferon to remain active in the body attacking the virus over a full week. Currently, there are two formulations of pegylated-interferon in clinical study: Pegasys (peginterferon alfa-2a) that has a larger PEG molecule (40kDa) attached to interferon, and PEG-Intron (peginterferon alfa-2b) that has a smaller molecule of PEG (12 kDa) attached to the protein.

The size of the PEG and other characteristics of pegylation influence the absorption, distribution, biologic activity, and also the ultimate degradation and elimination of interferon. The ability of the native protein to produce an immunologic response may be favorably altered by pegylation. PEG can be linked to interferon alfa by various amino acid residues and can be a linear or branched short chain or a long chain. All of these physical chemical properties may influence the response of the immune system to HCV and interferon and these differences may result in differences in the clinical response to therapy.

PEG-Intron has a linear monofunctional PEG molecule attached at several sites, and a PEG molecule combined to another adjacent interferon alpha. It is a lyophilized powder, stored at room temperature that needs to be reconstituted before each injection and the dosing is weight based (generally, 1.5 ug/kg weekly). It has an early peak after subcutaneous injection with an absorption half-life of 4.6 hours and a time to maximum concentration of 20 hours. The maximum concentration achieved is around 1 ng/ml with concentration tapering off and decreasing below 0 .5 ng/ml by 72 hours and continuing steadily with a decline thereafter.

Pegasys has a branched PEG chain of approximately 40,000 daltons, yet it maintains accessibility to the interferon alfa binding site, and has perhaps tighter binding. It is refrigerated, administered as a fixed dose (generally, 180 ug weekly), and is dispensed as a solution that can be injected without the need for reconstitution. Its half-life is greater than PEG-Intron at 50 hours with a time to maximum concentration of about 80 hours and sustained concentrations maintained for 168 hours or thereafter. Pegasys is not weight based dosed, but has been studied at a standard weekly dose.

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