Genotypes Explained

It is much easier to talk of the hepatitis C virus as if it is a single organism but in fact it is a range of viruses, similar enough to be called hepatitis C virus, yet different enough to be classified into subgroups.

Viruses are microscopic and no person could ever see them with the naked eye. Indeed, HCV is so small that there's been no confirmed actual sighting of it using any type of microscope yet developed.

Consequently, a better way to understand the terms HCV 'genotypes' and 'subtypes' is to compare them to things that we can more readily relate to.

The group of birds we call 'raptors' (birds of prey) have evolved into different main types. Imagining raptors as being hepatitis C viruses, you could take one major raptor type, such as eagles, and imagine these as being one of HCV's main types (genotypes).

But eagles as a group are made up of different sub types such as the American Bald Eagle and Australia's Wedge Tailed Eagle and Sea Eagle. You could imagine each of these as being one of the HCV subtypes that make up an HCV genotype.

Within each of above particular types of eagles, there are further differences. All Wedge Tailed Eagles, for example, differ from each other in regard to wing span, weight, colour, beak size, etc. Similarly, within a hepatitis C sub-type, individual viruses differ from each other ever so slightly. Such viral differences are not significant enough to form another sub-type but instead form what's known as quasi-species. It is believed that within an HCV sub-type, several million quasispecies may exist. Scientists predict that people who have hepatitis C, have billions of actual viruses circulating within their body. Although there may be one or two predominant sub-types, the infection as a whole is not a single entity and is composed of many different quasispecies.

Biologists are generally not known for creativity when it comes to naming things - hence hepatitis C virus. The most commonly used classification of hepatitis C virus has HCV divided into the following genotypes (main types): 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11. As we've highlighted, HCV genotypes can be broken down into sub-types, some of which include:

It is believed that the hepatitis C virus has evolved over a period of several thousand years. This would explain the current general global patterns of genotypes and subtypes:

1a - mostly found in North & South America; also common in Australia
1b - mostly found in Europe and Asia.
2a - is the most common genotype 2 in Japan and China.
2b - is the most common genotype 2 in the US and Northern Europe.
2c - the most common genotype 2 in Western and Southern Europe.
3a - highly prevalent here in Australia (40% of cases) and South Asia.
4a - highly prevalent in Egypt
4c - highly prevalent in Central Africa
5a - highly prevalent only in South Africa
6a - restricted to Hong Kong, Macau and Vietnam
7a and 7b - common in Thailand
8a, 8b & 9a - prevalent in Vietnam
10a & 11a - found in Indonesia

It's believed that of the estimated 160,000 Australians with HCV, approx. 35% have subtype '1a', 15% have '1b', 7% have '2', 35% have '3' (mostly being 3a). The remaining people would have other genotypes.

Current scientific belief is that factors such as duration of a person's HCV infection, their HCV viral load, age, grade of liver inflammation or stage of fibrosis may play an important role in determining response to interferon treatment. Recent studies have suggested that a person's HCV subtype (or subtypes) may influence their possible response to interferon, or interferon-ribavirin combination treatment. World-wide trials are being conducted which will soon shed more light on this belief. We'll publish any reports as they come to hand.

Genotypes and Genetic Variation of Hepatitis C Virus
by G. Maerterns & L. Stuyver,
reviewed by Dr Greg Dore
of the National Centre in HIV Epidemiology & Clinical Research.
From The Hep C Review; Ed 23, December 1998; Paul Harvey

The term "genotype" refers to HCV isolates from genetically
distinct groups, which have arisen during the evolution of this
virus. Hepatitis C virus demonstrates tremendous genetic diversity
which has wide-ranging implications for diagnosis and treatment of
HCV infection. Currently, there are six known hepatitis C
genotypes, each with numerous subtypes.

Genotype variation can be found worldwide. However, the relative
prevalence of different genotypes differs by geographic region. In
the United States, for example, genotype 1 is the most prevalent
whereas in Egypt genotype 4 accounts for the majority of
infections.

Determining the genotype of an individual patient's HCV isolate may
have important treatment implications. Of utmost clinical
significance is the role that genotypes play in response to
treatment and in determining the optimum duration of treatment. For
example, with all treatments tested to date, patients with
genotypes 2 and 3 are more than twice as likely as patients with
genotype 1 to achieve a sustained virologic response. In addition,
when using combination therapy consisting of interferon and
ribavirin, a 24-week course is recommended for genotypes 2 or 3
compared to 48 weeks for patients with genotype 1. Although the
significance of genotype in treatment response is clear, the
influence of genotype on the severity of liver damage and the rate
of disease progression has not been well defined. Most
investigations suggest one viral genotype is no more virulent than
any other, and that other factors are responsible for the variation
seen in medical outcomes of chronic hepatitis C infection.

Within an individual viral isolate identified as a particular
genotype, further genetic heterogeneity exists. Through spontaneous
mutations, closely related yet significantly different viral
genomes evolve over time. These are known as quasispecies.
Production of quasispecies is likely to be important in the natural
history of hepatitis C infection, since diversification is believed
to be one mechanism by which the virus escapes the immune response
of the host. Quasispecies differ from genotypes in that genotypes
represent major genetic differences that vary in geographic
distribution and epidemiologic associations, whereas quasispecies
represent minor genetic differences in an individual infected with
a single genotype. Quasispecies change in an individual over time,
whereas genotypes do not. Quasispecies can be measured
quantitatively (viral complexity) and qualitatively (viral
divergence over time) although such tests are not currently
available as clinical tools.

HCV quasispecies have a number of important implications for
practicing clinicians who treat HCV infection. A recent study1
demonstrated that during acute HCV infection, isolates which
developed little genetic diversity in a particular region of the
viral genome were associated with self-limited hepatitis, whereas
the development of persistent infection was associated with the
evolution of greater genetic diversity in this region. Thus, the
dynamics of quasispecies evolution during acute infection may be an
important determinant of host immune response and the future course
of infection. HCV variants also can be used to prove linkage of
infections that are associated epidemiologically. For example,
molecular analysis has been used to link mother/infant pairs, to
define HCV in apparently concordant sexual couples as virologically
concordant or discordant, to prove nosocomial transmission of HCV
between health care provider and patient, and to link needle stick
recipients with the sources of infection.
References