Hepatitis C and Ozone Therapy

Hepatitis C (HCV) is a global disease with an expanding incidence and prevalence base. Of massive public health importance, hepatitis C presents supremely challenging problems in view of its adaptability and its pathogenic capacity. The unique strategies that HCV utilizes to parasitize its host make it a formidable enemy and therapeutic interventions need considerable honing to counter its progress. Ozone, because of its special biological properties, has theoretical and practical attributes to make it a potent HCV inactivator.

History of the virus A form of hepatitis became recognized in the 1970's that resembled hepatitis B, serum hepatitis, and to a lesser extent hepatitis A, infectious hepatitis. It had, however, novel features, amongst them, a distinctive serological profile. In 1989, the genome of hepatitis C (HCV) was deciphered.

It is possible, by means of extrapolation from the genetic evolution of a virus, to approximate its age. Sequence genetic analysis points to the diversification of different HCV genotypes 200 to 400 years ago. Ancestors to these genotypes probably date back 100,000 or so years when viruses co-evolved with modern humans. Further analysis of genetic viral trees and Old and New World primates take the primordial forms of these viruses to primate speciation periods some 35 million years ago.

It is possible, by means of extrapolation from the genetic evolution of a virus, to approximate its age. Sequence genetic analysis points to the diversification of different HCV genotypes 200 to 400 years ago. Ancestors to these genotypes probably date back 100,000 or so years when viruses co-evolved with modern humans. Further analysis of genetic viral trees and Old and New World primates take the primordial forms of these viruses to primate speciation periods some 35 million years ago.

Virion architecture and molecular biology The HCV particle is composed of a nucleocapsid containing its genome, an RNA single strand composed of approximately 9600 nucleotides, and its protein coating. The nucleocapsid is surrounded by an envelope which allows attachment and penetration into host cells. The genome encodes structural proteins designated as core (C), envelope 1 (E1), envelope 2 (E2), and P7 (unknown function), providing for virion architecture, and nonstructural proteins, mainly enzymes essential to the virion's life cycle, designated as NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Proteases release structural and nonstructural proteins. Helicases unwind viral nucleic acid. Polymerases replicate RNA. Within this genome is located a hypervariable region implying an area of intensive genetic fluidity and mutational potential. HCV displays great genotypic flexibility which makes for sophisticated evasiveness to host defenses.

The nucleocapsid is surrounded by an envelope, a lipid bilayer associated with a union of carbohydrates and proteins, glycoproteins. Up to 60% of the lipid component of the envelope is phospholipid and the remainder is mostly cholesterol. It possesses projections called peplomers which facilitate attachment to host cells. One protein on peplomers of the HCV particle which is thought to be instrumental in the attachment process is designated CD-81.

The sequence of nucleotides within the HCV genome shows significant variations. Strains obtained from different parts of the world, for example, may differ substantially in their structural and nonstructural protein compositions. This has lead to a system of classification of the HCV family into 6 genotypes (1 to 6), and approximately 100 subtypes (designated a, b, c, ect.). Genotypes vary from each other by a factor of 30% over the entire genome. Subtypes vary by about 20%. Genotypes 1 to 3 have global distribution, while genotype 4 and 5 are found mainly in Africa, and 6 is distributed in Asia. Importantly, genotype and subtype differences have shown varying susceptibility to antiviral therapy.

Within any one afflicted individual, HCV particles do not show a homogeneous population. Instead, they function as a pool of genetically variant strains known as quasispecies. This is due to the high replication error inherent in the function of the polymerase enzymes. Herein lies one of the important armaments of HCV. Continuously generated genetic diversity gives it great advantage in negotiating and conquering immune defense and therapeutic strategies. Furthermore, the antigenic differences between genotypes may have implications regarding the proper evaluation and the therapeutic regimen of patients.

Viral life cycle A freely circulating virion enters a host cell by binding to a cell surface receptor. In the case of HCV the host cell is a hepatocyte. However, bone marrow, kidney cells, macrophages, lymphocytes, and granulocytes may also be trespassed.

Once cell entry is achieved, the virion sheds its envelope to commence its replication. It binds to cellular ribosomes and released viral polymerase begins the RNA replication cycle. Newly formed nucleocapsids continue their assembly with the acquisition of new envelopes by means of budding through membranes of the cell's endoplamic reticulum. Newly formed virions may number in the range of 10 billion daily. The average life span of virions is in the order of a few hours.

Virions are then released into the general blood and lymphatic circulation, ready to infect new cells, re-infect already diseased cells, or a new host, mainly through bodily fluid transmission pathways. HCV RNA, as measured by polymerase chain reaction (PCR) may show 10 million or more virions per ml. As little as 0.0001 ml of blood may be sufficient to impart infection. The evolution of hepatitis C is characterized by phases of accentuated viremia punctuated by periods of relative quiescence. The presence and timely detection of these viremic waves may offer novel therapeutic considerations.

Clinical and laboratory manifestations Hepatitis, from anyone of the several viruses capable of inducing liver inflammation, produce a spectrum of clinical and laboratory manifestations. Hepatitis C distinguishes itself by the low incidence of acute phases and by the high incidence of progression to chronicity. Acute hepatitis C progresses from exposure, to incubation, to pre-icteric, icteric, and convalescent phases. With an incubation period of about 6 weeks, the first and sometimes only symptoms include weakness, fatigue, indolence, headache, nausea, poor appetite, and vague abdominal pain. The pre-icteric period extends from the onset of symptoms to the appearance of jaundice, ranging usually from 2 to 12 days. The icteric phase corresponds to the declaration of jaundice and darkened urine. The convalescent phase is marked by the gradual disappearance of symptoms.

Clinical and laboratory manifestations Hepatitis, from anyone of the several viruses capable of inducing liver inflammation, produce a spectrum of clinical and laboratory manifestations. Hepatitis C distinguishes itself by the low incidence of acute phases and by the high incidence of progression to chronicity. Acute hepatitis C progresses from exposure, to incubation, to pre-icteric, icteric, and convalescent phases. With an incubation period of about 6 weeks, the first and sometimes only symptoms include weakness, fatigue, indolence, headache, nausea, poor appetite, and vague abdominal pain. The pre-icteric period extends from the onset of symptoms to the appearance of jaundice, ranging usually from 2 to 12 days. The icteric phase corresponds to the declaration of jaundice and darkened urine. The convalescent phase is marked by the gradual disappearance of symptoms.

Hepatitis C can only be distinguished from other viral hepatic conditions by serological and virological determinations. Liver enzymes characteristically affected by HCV infection include serum alanine transfesferase (ALT), aspartate aminotransferase (AST), gamma- glutamyl transpeptidase (GGTP), and alkaline phosphatase; in addition, there may be abnormalities in bilirubin, serum albumin, prothrombin time, and platelet density.

Cirrhosis, a diffuse disruption of liver tissue architecture with regenerative nodules surrounded by fibrosis, is an important sequel to hepatitis C. Within 20 years post HCV infection 20 to 25% of patients will develop cirrhosis. Hepatic decompensation ensues with ascites as the salient marker.