With the development of antibodies against the viral e-antigen (anti-HBe) or HBeAg seroconversion, the immune-control phase (inactive chronic HBV where HBV DNA levels are low or negative and ALT levels are normal) begins. This quiescent stage, however, is by no means permanent. Disturbances in the balance between viral and immune-system activity may lead to reactivation of the virus; this is the immune-escape phase (active HBeAg-negative disease) where viral loads and liver-enzyme levels, again, predictably increase. Active e-negative disease is also seen when the patient's immune system mounts a response that is not strong enough to completely suppress viral replication; in effect, the inflammatory process persists, with HBV DNA elevations less than in the e-positive phases.

T
reatment guidelines

    The American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver have established treatment guidelines for the management of CHB. No treatment is necessary when ALT levels are normal and HBV-DNA levels are below 100,000 cp/mL (20,000 IU/mL); close follow-up is, however, imperative. For grossly elevated ALTs (>2 x ULN) and high viral loads (>100,000 cp/mL), treatment is given when no spontaneous seroconversion occurs in three to six months. But, if the liver is overtly decompensated, urgent treatment is required.

    The guidelines for HBeAg-negative disease are quite similar, with a few modifications. Said Sollano: "You can have patients with lower viral load and ALTs just above normal. These patients might need to have liver biopsies."

    For those who need to be treated, either nucleoside analogs (NA) or interferon therapies are given to help eliminate the virus, maintain viral inactivity, and prevent relapse or reactivation. In the short run, oral antivirals are easier to give and cause fewer side effects compared with subcutaneous interferon therapies. Antivirals also provide potent HBV-DNA suppression, although this does not necessarily translate to the desired HBeAg and HBsAg seroconversion-effects that are more commonly seen with interferon therapies. Interferon, apart from its immune-boosting function, also possesses antiviral properties. Drug fatigue, usually seen with antivirals because of their indefinite duration of treatment, is rarely encountered with interferon strategies.

    "(HBeAg)/anti-HBe seroconversion, at the moment, is the benchmark of success of therapy," said Sollano. Seroconverters have longer survival rates and experience fewer complications. Collated clinical trials from 2005-2006 on HBeAg-positive patients show that 20 percent of patients on antiviral regimens 27 percent of those on peg IFN (pegylated interferon), and 18 percent on conventional IFNa seroconvert after one year. At two years, around 30 percent of patients on both antiviral drugs and interferon therapies clear their HBeAg and produce anti-HBe.

    Recent AASLD guidelines for the treatment of e-antigen-positive CHB recommend giving IFN for four to six months, pegIFN for six months to one year, and antiviral agents for at least a year. The Keefe Algorithm suggests that treatment be continued for six to 12 months after seroconversion and viral loads are no longer detectable by polymerase chain reaction (PCR).

    E-antigen-positive patients who have high pretreatment ALT-indicative of robust immune response or moderate to severe hepatitis-are responsive to interferon and oral agents like lamivudine and adefovir. Better response to conventional interferon and lamivudine are seen in patients with low pretreatment HBV DNA. Genotype B (v. C), genotype A (v. D), and infection as an adult also predict better response to interferon.

    For HBeAg-negative CHB, the AASLD 2007 guidelines suggest that interferon be given for one year. Lamivudine, adefovir, entecavir, and telbivudine should all be given for more than one year.

    HBe-Ag negative is the predominant CHB form in Europe; its prevalence in Asia is also steadily rising. "It is a difficult disease to treat because the tendency to relapse is very high," noted Sollano. Studies showed that at doses between six to 10 MIU three times a week, given from four months to two years, conventional interferon dramatically reduced HBV DNA to undetectable levels and normalized ALT in 28 to 69 percent of e-negative patients. Sustained response is seen in as high as a third of patients. Even HBsAg loss-an outcome not seen with NA-is demonstrated in 4.5 to 13 percent.

    Given the different mechanisms of action of NA and interferon, combination therapy is being explored. Recent research demonstrated that the problems with resistance may be reduced when nucleoside treatment is coupled with interferon therapy. "Maybe, combination therapy is for the future," said Sollano. "If you are going to suppress the virus up to a certain concentration (with NA), you are able to kick CD8 and CD4 values, maybe that's the best time to put interferon in your therapy.... We know that these are conceptually acceptable strategies, we only need to document the clinical outcomes of these experiments."

Balancing efficacy, safety, and cost

    Although efficacy and safety are very important concerns, cost is also important, and has become a major hindrance to initiation of immune-based treatments in the country. The addition of Uniferon, a high-quality and inexpensive interferon-a2b to the list of immunomodulating agents is a welcome boost in the fight against CHB infection.

    "Safety is quality," said Strang. With Uniferon, there is a "low risk of pyrogenicity and antigenicity, no risk of blood-transmitted diseases, and [there is] high stability."

    The final recombinant interferon passes through four purification processes-three steps more than the standards set by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products-before it is marketed.

    Compared with other interferon therapies, Uniferon causes fever to a lesser degree because Pseudomonas putida, a bacterium without a fever-inducing lipopolysaccharide coat, is the cell used instead of the commonly utilized E. coli. Moreover, said Strang, "it is considered as a good manufacturing organism.... It's an extremely safe bacterium; ... E. coli is not."

    To reduce antigenicity, one has to lower aggregates or improperly folded proteins. When Uniferon was being developed 20 years ago, a "genetic construction that allows a constitutive production of interferon" within the periplasm-the space between the outer and inner membranes of the cell-was devised. Protein products, therefore, accumulate, not within the cytoplasm where around 10 percent of the proteins are improperly folded and form aggregates. As proof of this purity, 99 percent of Uniferon is in monomeric form. As a result, there are very few inactive molecules.

    When the molecule is passed from the cytoplasm to the periplasm, methionine is automatically cut off from the amino-acid chain. The bacteria remove the methionine, meaning no cyanogen bromide is needed to remove methionine; nature takes its normal course.

    With Uniferon, there is also reduced risk for blood-borne diseases because dextran, instead of albumin, is used as stabilizer. The use of albumin introduces the risk of blood contamination, whereas dextran, a plasma expander, is very safe.

    Uniferon is also highly stable, with a three-year shelf life. The combined benefits of the interferon's unique formulation and its purity contribute to its stability. Isoelectric focusing, among other techniques, shows that Uniferon is uncontaminated. "In terms of purity of the product, we have a higher product than the European pharmacopoeia requirement," said Strang.

    Uniferon is manufactured by Sicor Biotech in Lithuania and marketed in the Philippines by Getz Pharma. Getz Pharma, a progressive subsidiary of the United States-based Getz group of companies, is an international generic-pharmaceutical corporation with a strong prescence in the Asian region. M

 

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