Stop copying, stop resistance!
New hepa B treatment strategies aim to suppress HBV replication, prevent escape mutations
The World Health Organization estimates that hepatitis B, a serious global malady, is responsible for one million deaths annually. It is also the leading cause of liver cancer worldwide. Although a vaccine is available, it is not useful for individuals already chronically infected. To determine the best ways to deal with chronic hepatitis B, a panel of American specialists published new treatment guidelines in Clinical Gastroenterology and Hepatology last year.
According to the guidelines, the goal of therapy is to "to eliminate or significantly suppress HBV replication and prevent the progression of liver disease to cirrhosis and the potential development of liver failure or hepatocellular carcinoma."
One drug that recent studies show offers hope for achieving this is adefovir dipivoxil (Hepsera). Dr. Jose Sollano, head of the section of gastroenterology of the University of Santo Tomas Hospital, and Prof. Young-Hwa Chung of the Asan Medical Center and the University of Ulsan College of Medicine presented the results of these studies in a symposium organized by GlaxoSmithKline in last year's convention of the Philippine Society of Gastroenterology.
Phase-III trial
Forty-eight-week treatment with adefovir dipivoxil 10 mg results in statistically significant improvement in liver histology, reduction in serum HBV-DNA level and degree of necroinflammation, and alanine aminotransferase (ALT) normalization among HBeAg-positive and HBeAg-negative patients, according to Sollano, citing results of the pivotal phase-III international trial. The results of the 48-week trial were published in the New England Journal of Medicine.
Serum ALT normalization was achieved in 48 percent of HBeAg-positive (p<0.001) and 72 percent of HBeAg-negative patients (p<0.001).
Sollano said HBeAg loss and seroconver-sion rates were "substantial" compared with those that have been recorded for lamivudine, noting that the seroconversion with adefovir dipivoxil was "more permanent." He also noted that the reduction in serum HBV-DNA was similar regardless of genotype, and the same improvements in histological, virological, and biochemical parameters were seen among Asian and Caucasian patients.
Sollano reported that the durability of seroconversion with adefovir dipivoxil has also been shown by Chang et al. in a multicenter, long-term, off-treatment observational study of 66 patients who developed HBeAg antibody after treatment was stopped. The results showed that during follow-up (5 to 114 weeks) 91 percent of the patients who developed anti-HBe antibody remained positive for antibody at a mean of 55 weeks off-treatment.
Another factor to look at in hepatitis B management is the cccDNA, reduction of which, Sollano said, "might be the key to curing hepatitis because, at the moment, you can control the replication but you cannot drive away the virus." In an off-treatment study by Werle et al., 48-week treatment with adefovir dipivoxil resulted in an 84-percent reduction of cccDNA and 98-percent reduction of total intracellular HBV-DNA.
Overcoming resistance
One big challenge in the management of chronic hepatitis B is antiviral resistance, which often develops with long-term use of lamivudine, said Chung. "About 30 to 40 percent of patients experience resistance during long-term (24 months) lamivudine therapy," he said, noting that most cases are associated with YMDD mutants.
Chung said adefovir dipivoxil presents an effective therapeutic option in cases of lamivudine resistance associated with YMDD mutation. The rarity of associated escape mutations (three to four percent in two years) is its most important advantage yet. In addition to activity at the site of lamivudine action, which is inhibition of encapsidation and DNA polymerization, it also inhibits the intracellular production of cccDNA.
Perillo et al. (2004) demonstrated that 85 percent of patients who had YMDD mutants treated with adefovir dipivoxil in addition to lamivudine showed excellent HBV-DNA responses. Among the responders, 20 percent reached PCR negativity, 15 percent lost serum HBeAg action, and 30 percent achieved serum ALT normalization. "These figures were much higher than in the lamivudine and placebo groups," noted Chung.
Chung said development of resistance to adefovir dipivoxil is infrequent and delayed during long-term therapy (less than four percent over three years). The tridimensional structural similarity between adefovir diphosphate and the natural substrate dATP may be responsible for the rare escape mutation. In vitro and preliminary data suggest that the mutations at rtN236T and rtA181V remain susceptible to lamivudine, he added.
As for safety, Sollano noted that adverse events with adefovir dipivoxil in the phase-III trial were comparable to those of placebo. At the 10 mg dose, no increase in creatinine level over 0.5 mg/dL was noted among the patients. There were also no changes in serum phosphorus levels.
The best action against nephrotoxicity is constant monitoring, Sollano stressed. "Renal toxicity is perhaps related to dose. It is important to monitor renal function while on treatment, particularly [for patients] with preexisting risks for renal impairment."
To prevent ALT elevation during crossover from lamivudine to adefovir dipivoxil, Sollano suggests "overlapping treatment with lamivudine for a few weeks."
Yeast of our worries
From unobtrusive hitchhikers, yeast or fungi transform into enemies, given the right circumstance
Yeast and fungi are some of the oldest organisms on earth. They're everywhere--inside and outside our body. Yeast is a one-celled fungus, unchanged genetically for millions of years, while fungus is a spore-producing organism, single-celled or multicellular, without chlorophyll, that lives by absorbing nutrients from organic matter. Mildew, molds, mushrooms, rust, smut, and yeast are just a few examples.
They are also the earth's garbage recycler as they break down dead organic matter into its basic elements. From a one-celled organism, fungi could grow to monstrous proportions if nourished too well.
In 2000, an almost 3,000-year-old tree-root fungus, Armillaria ostoyae, was discovered in the Malheur National Forest in Oregon, United States. Besides its age, its size was also notable. It covered 890 hectares of land, shooting out shoestring-like structures called rhizomorphs across tree roots and through the soil--making it probably the largest living organism on earth.
Yeast or fungi in our bodies are usually benign. We breathe them in and out. In our guts, they're normally a colony that ferments sugar.
However, when our bodies become out of balance, like when our immune system is weakened or when use of antibiotics kills off too many of the bacteria that keep them in check, its dark side emerges. It proliferates and sprouts nutrient-absorbing filaments (rhizoids) and become fungus or yeast infections.
Candida albicans, which normally inhabits the mucous membranes (gut, mouth, vagina), is common yeast. Its overgrowth results in candidiasis or thrush. Candidiasis commonly manifests as itching and discharge in the genitals. It is common in women but can also happen in men, especially uncircumcised ones. Thrush is characterized by creamy-white, curd-like patches on the tongue.
Fungus is also a major allergen and culprit in chronic sinusitis. The US Department of HeALTh and National Institute of Allergy and Infectious Diseases of the National Institutes of HeALTh reported in 2004 that chronic sinusitis sufferers have enhanced immune responses to fungi, involving both Th1 and Th2 cytokines.
Fungal infections could be body- or system-wide, without us realizing it--symptoms are subtle and difficult to attribute to a particular disease. They could also be ruthlessly fast. In January 1995, Discover magazine came out with a story on mucormycosis, fungal infection of the sinus, on a diabetic middle-aged woman. Though very rare, it is fatal in most cases. The fungi that cause mucormycosis thrive in warm sugary environment. The immune defense of most diabetics is up to the task of preventing the fungi from taking hold but, in the unlucky few, the fungi would eat its way through the nasal passages into the sinuses, face, skull, and brain in a matter of months.
Mushrooming infections
Of about 50,000 species of fungi, only 50 to 75 are pathogenic in humans. In recent years, the incidence of fungal infections has sharply increased.
Primarily, this is because clinicians are more aware of them and have improved diagnostic methods. However, since certain species of yeast or fungi are opportunistic, the growing cases of acquired immunodeficiency syndrome (AIDS) and diabetes, number of transplantation operations and radiation treatment, and use of immunosuppressive drugs have also resulted in increasing secondary infections from fungi.
Infections can be mild, involving only the skin, hair or nails; or it can invade internal organs especially the lungs; or it can spread throughout the system.
Aside from the direct method for superficial and skin infections, culturing of appropriate specimens, microscopic examination of biopsied tissue, examination of blood serum for the presence of certain antibodies, skin testing with specific fungal antigens, and use of ultraviolet light can help determine fungal infections.
Superficial infections, like ringworm and athlete's foot, are usually not serious through chronic. With improvement of personal hygiene and barring an immunocompromised condition, they clear up spontaneously.
Fungal infections of subcutaneous tissues or internal organs, which are chronic and can be fatal, are rarely seen in practice. They require a prolonged systemic antifungal therapy that may even prove to be ineffective. Agricultural workers, gardeners, and laborers who work with soil can be vulnerable to these deep infections.
Meanwhile, most cases of histoplasmosis and other systemic fungal infections are reported in Midwestern United States, though sporadic cases have been reported here--in infants and adults.
Those infected may not even know they are infected for a long time. When symptoms develop, the lungs, oral mucosa, skin, and other tissues are affected. Antifungals have been used with favorable results.
Fungi that are otherwise harmless in heALThy individual can turn deadly in people with AIDS, who often develop pneumocystis pneumonia and other fungal infections. Fungi from the genus Cryptococcus can also cause meningitis in AIDS patients.
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