Only explicitly identified in 1989 HCV is classified as a flavivirus. Prior to this it was known to exist and was usually described as non-A, non-B hepatitis. The virus replicates quite inaccurately and so results in a very high level of mutation. Rates of co-infection with HIV vary in Britain with the largest HIV clinic suggesting a figure of nearly 10%.

Hepatitis C is the most common type of viral hepatitis in the UK, affecting almost every adult with haemophilia, a majority of IDUs and an increasing number of gay men. It is also a significant problem worldwide and because of the similarity of the transmission routes a major concern for people with HIV. The UK Government estimate the number of people chronically infected with hepatitis C to be around 200,000 the majority of whom are currently unaware of their infection (Hepatitis C Strategy for England 2002). Other groups have estimated the number to be as high as 400,000.

HCV is a highly variable disease with major differences in how aggressive it is, what symptoms it causes and how it responds to treatment. HCV is a long lasting disease and once established as chronic it appears to remain in the body for life. Although generally a slow acting condition, usually taking decades to cause cirrhosis and liver failure in people, it can significantly damage the liver within a few years for others. Some people experience almost no symptoms from it while others are significantly incapacitated. Fatigue, abdominal pain and nausea are the most common symptoms but there are many others and not all are confined to the liver.

Hepatitis C is both immunopathic and cytopathic. Cytopathic means the virus causes damage directly, by injuring the cells that it infects while immunopathic means that it is the response of the body's immune system to the viruses that causes the damage. It is because HCV causes both mechanisms of injury to cells that the symptoms are so varied. HCV is described as being hepatotropic and lymphatotropic, meaning that it inhabits both the liver and the lymphatic system. People with HCV have a higher likelihood of getting Hepatocellular Carcinoma (HCC) better known as liver cancer and possibly are at greater risk of non-Hodgkin's lymphoma. It remains uncertain if hepatitis C affects the progression of HIV.

Disease progression

Less than a third of people suffer an acute phase at the time of infection with symptoms usually including jaundice and fatigue but less severely than for HBV. A small number of people also clear the virus naturally after the development of anti-bodies. The vast majority of people suffer from chronic infection and most experience no noticeable symptoms at the time of infection.

Currently it is not known what proportion of HCV patients will go on to experience the various symptoms associated with liver disease, let alone the other categories of illness. The figures that have appeared, claiming to show breakdowns of patients progressing to cirrhosis or liver cancer are misleading and are based upon current cross sections of patients rather than long term follow-up of infected patients.

Leading hepatologists often cite 20% as the proportion progressing to serious liver disease. However other analyses conclude that progression occurs across the whole HCV-positive population at differing speeds (Dienstag), and suggests that HCV can cause other life threatening conditions. Precise breakdowns of proportions progressing to various types and stages of disease are still a matter of conjecture.

Certain factors have been identified as speeding up the progression to fibrosis and cirrhosis and others that originally appeared likely have been shown not to. A number of others remain unproven or only hinted at by research data.

Factors related to the virus

• Duration of infection: the risk of liver disease increases with time. There is no time point beyond which one can say 'If I haven't got liver disease now, I never will'.
• Genotype: It seems that the different genotypes may affect the course of the disease in people. For example genotype 3 appears to be the easiest for the body to clear but may progress to fibrosis faster and genotype 4 may be harder for the body to clear than the other major genotypes. This is however a complex area and past assertions about some genotypes being more virulent were later refuted so this may change again.
• Viral load: unlike in HIV infection, a high viral load prior to treatment does not predict a faster or more severe disease progression and may be entirely unrelated.

Factors related to the person

• Age at infection: Contracting hepatitis C after age 40 has been associated with greater risk of progression in some studies.
• Alcohol consumption:  An increased risk of cirrhosis is associated with sustained alcohol consumption of greater than 40g each day. 40g of alcohol is five units or two pints of most lagers.
• Your own genetic make-up.
• HIV infection and a low CD4 count: A CD4 count of less than 200 is associated with an increased risk of cirrhosis; those with higher CD4 counts were at no greater risk than their HIV-negative counterparts, suggesting that immune suppression facilitates liver disease.
• Other hepatitis viruses: Co-infection with hepatitis A or hepatitis B increases the risk of liver disease.
• Gender: men seem to progress faster to liver disease.

All of these effects only show themselves across a population and so whilst a young woman with a healthy lifestyle will be unlikely to quickly develop serious liver disease it is no guarantee. Most of these factors are also beyond the control of a person as no one can change their age or genetic make up. Reducing alcohol consumption and avoiding other hepatitis infections are the only things that are truly within the control of a person. How someone responds to this is up to the individual and whilst not drinking alcohol may be fine for one person it may remove a significant social support structure for others. People with HCV may also chose to drink fully aware of the consequences for their health just as smokers are almost always aware of the likely impact on their future health of smoking.

Transmission

Hepatitis C has a number of routes of transmission. Transmission by injection is the most common route but infections of HCV through sex is a particular issue for gay men with HIV. Co-infection with HIV has also been shown to increase the infectivity of people with hepatitis C.

Injection drug use

Hepatitis C is easily passed on in situations of intravenous drug use. HCV is spread via the sharing of spoons, filters and other paraphernalia as well as hypodermic needles and syringes.

Overall HCV infection rates of IDUs are extremely high varying between 60%; and 77% in studies in the UK. In 2000 the Department of Health estimated that one-third of IDUs attending GUM clinics in England and Wales were infected with HCV, of which only 40% were aware of their infection. The prevalence of HCV among injecting drug users varied by region, the highest numbers being in London and the North West.

One-in-12 IDUs who began injecting in the past three years were HCV-positive.  IDUs who had been in prison were almost twice as likely to have been infected with HCV than those who had not.

Sexual transmission

HCV can and is transmitted sexually but seems to happen most frequently between HIV positive men who have sex with men. Sexual transmission among heterosexuals who do not have HIV appears extremely unlikely by comparison (Marincovich 2003). The amount of circulating hepatitis C in the blood stream is significantly increased in people with HIV (Eyster 1994) and this may mean they are more infectious in sexual situations. The impact of HIV on the immune system may also mean that people with HIV are more likely to be contract HCV sexually from someone infected and it may be the combination of these two factors that leads to the noticeable increase in sexual transmission rates.

Outbreaks of acute HCV have been seen in London and Paris among gay men attending HIV clinics and sex seems to be the route of transmission. Researchers from Naples found that HCV infection was almost three times higher in those who were HIV-positive compared to HIV-negative controls (15.1% versus 5.2%; P = 0.005). Significantly,18.7% of those who had regular heterosexual or gay sex with an HIV+ partner were HCV+, compared with only 1.6% for partners of HIV-negative controls (Filippini 2001).

Abresica (2002) from Italy found that 20% of women who had been infected with HIV by HIV/HCV co-infected partners were also infected with HCV, leading the co-authors to conclude: "It's probable that HIV and its related opportunistic infections of female genital tract could strongly facilitate HCV sexual transmission." However other retrospective studies have found little or no sexual transmission of HCV among heterosexual couples where one had HIV (e.g. Marincovich 2003).

Research suggests also that sexual practices which involve contact with blood are associated with hepatitis C transmission. These include unprotected anal sex, sex during menstruation and fisting.

Occupational exposure

As with hepatitis B and HIV there is the risk of exposure in healthcare settings from needle stick injuries. The transmission rate has been found to vary between 0.4% and 2% (from 1 in 250 to 1 in 50). The rate for HIV is between 0.2 and 0.4% (from 1 in 500 to 1 in 250) (University of Virginia 2001)

Vertical transmission

Estimates of the rate of mother to baby transmission of HCV range from 0% to 36%, but the risk of transmission appears to be increased in mothers who are co-infected with HCV and HIV. This may be due to the generally higher HCV viral load in people co-infected.

Most transmission is known to occur around the time of delivery, and planned Caesarean section, before the rupture of membranes, lowers transmission rates compared to emergency Caesarean or vaginal delivery. (Gibb 2002)

Breastfeeding is not considered to be a route of transmission, and in the United States the Centers for Disease Control do not consider bottle feeding of uninfected infants to be necessary. Bleeding or cracked nipples are a theoretical route of transmission.

Household contact:

Sharing any piece of equipment that are likely to get blood on them such as razors or toothbrushes is a definite but small risk for transmission of hepatitis C.

Intra-mucosally: sharing rolled-up notes to snort cocaine

According to a large scale American survey of over 500,000 blood donors risks of exposure to HCV were associated with intra-nasal cocaine use. The results of this survey do not amount to proof of intra-nasal transmission in themselves, but rather a correlation (Conty-Cantilena 1996). A study from the Royal Free also supported the idea that this is a route of transmission (Danta 2003).

Blood transfusions and blood products

The very high rates of HCV infection in haemophiliacs, particularly those treated prior to the introduction of donor and blood screening and sterilisation in 1986, reflect the ease of transmission via this route (UKHCDO 2004). A small number of people have also contracted HCV from blood transfusions and organ transplants. The Skipton Fund has been setup to provide a two stage financial payment to people infected with HCV in the UK from medical treatment.

Vaccination programmes and traditional acupuncture

It is now known that large numbers of people were infected with HCV by 'shared needle' vaccination programmes, particularly in Southern Europe, Asia and Africa. It has been particularly blamed as the reason for the huge number of infections in Egypt. Acupuncture may have also spread the virus in Asia prior to the introduction of sterilisation techniques.

Cosmetics and tattoos

A small percentage of the HCV-positive population have been infected by cosmetic contact. Practices that can lead to the drawing of blood including tattooing, piercing and shaving are assumed to be responsible.

Tests for HCV

Exposure to HCV but not chronic infection is shown by an HCV antibody test.  As some people naturally clear the virus from their body chronic infection is only diagnosed in people who test positive to a PCR test. The PCR test is similar to a viral load test for HIV in that it detects that the virus is present in the blood. It may also be called an HCV RNA test. Antibodies to HCV do not mean someone is immune to HCV in future if they have naturally cleared the virus or have been successfully treated.

HIV can cause the antibodies to HCV to disappear in some people, a factor which may have caused some people with HIV to have tested negative for HCV in the past. If hepatitis C infection is suspected, because someone has jaundice or their liver function tests suggest inflammation, then the HCV PCR test should be carried out (BHIVA 2004b).

The standard liver function tests mentioned at the start of the chapter are also used to help define whether the person has liver damage.

Genotypes are the different types of a virus that occur. The genotype test for HCV is an important one for people who are going to have treatment. There are six major genotypes with others that are only found in specific parts of the world and are labelled numerically, 1-6. Some genotypes are further divided into subtypes such as 1a and 1b. Genotype 1 is the most common in the United States, accounting for more than 75% of all infections. Genotype 3 is the most frequent on the Indian subcontinent. Most infections in Egypt are genotype 4 whilst genotype 5 is usually only in southern Africa. Genotype 6 is found in Southeast Asia.

In the UK, it is thought that about two-thirds of people infected have genotype 1, most of the rest being 2 or 3. Genotypes 2 and 3 respond better to current therapy than genotypes 1 and 4. Much less is known about the response to treatment of genotypes 5 and 6.

Treatment

Treatments dependent on a number of factors. The results of the biopsies and liver function tests along with how a person is feeling are used to decide whether treatment is recommended or not. Since many people can live for decades without symptoms or significant liver damage, treatment is not always recommended to or wanted by people. The treatment is currently pegylated interferon and ribavirin. Pegylated interferon is a once-a-week injection and ribavirin a tablet taken twice a day. It is an arduous treatment, usually causing many side-effects which can significantly debilitate people. Almost all the side-effects disappear when treatment stops, but a few can be permanent.

This is a treatment that is taken for a set period of time and either cures people of HCV or fails to. If the treatment has little or no impact on the level of hepatitis C in the bloodstream after twelve weeks, it is stopped. If it does significantly reduce the level of virus, preferably to a level below detection, treatment continues to the end of the course.

The length of time a person takes treatment currently depends on the genotype. People who do not have HIV and those with genotypes 2 and 3 require treatment for 24 weeks, while those with other genotypes generally take treatment for 48 weeks. Some people respond to the medication when they are taking it, but it does not completely eradicate the virus from their system and it reappears in the bloodstream once the treatment programme has finished. This is often described as a partial response. People for whom the treatment cures them of HCV are described as sustained responders as their response to medication is sustained beyond the treatment programme. Three quarters of people with HCV genotypes 2 and 3 are cured by Pegylated Interferon and Ribavirin and just over half of those with genotype 1.

In people co-infected with HIV as well, treatment can become more important as the chance to remove HCV may reduce the load on a liver that may have to deal with metabolising HIV therapies as well. Current expert opinion is that treatment of Pegylated Interferon and Ribavirin should be extended for people with HIV. People with Genotypes 2 and 3 taking treatment for 48 weeks and 72 weeks of treatment for the other genotypes. This opinion comes from the poorer results seen in people with HIV and HCV who took the treatment for the standard lengths of time.

In the largest trial of pegylated interferon and ribavirin in coinfected people so far done, the APRICOT trial (Torriani 2004), the sustained response rate overall was 40% after 48 weeks of treatment but there was a big difference between genotypes 2 and 3, where 62% of patients responded, and genotype 1, where only 29% had a sustained response.

This difference was even more pronounced in a smaller study, ACTG 5071 (Chung), which only found a sustained response rate of 27%, and 14% in people with genotype 1, but 75% in genotype 2 and 3.

For those with cirrhosis or liver failure, transplantation is viable treatment if the person's HIV prognosis is good. For a complete discussion of current therapeutic options for HIV-HCV co-infected individuals, see the HIV & AIDS Treatments Directory.

Is there a vaccine?

Epidemiology

Worldwide the number of people with chronic hepatitis C has been estimated at 170 million, although some estimates are as high at 400 million. The highest prevalence rates appear to be in Asia and Africa. In the USA, the prevalence is thought to be about 1.8% of the general population (approximately five million people), although a 2002 study found that HCV prevalence in a cohort of military veterans in New York was 10.6%.

In Europe, the infection rate is at its lowest in the northern of the continent, with prevalence rates generally rising in the south and east. Data from the EuroSIDA cohort of European people with HIV indicate that 33% were co-infected with HCV, and among injecting drug users the rate increased to over 75%. (Stubbe). The UK estimate of 200,000 people infected equates to a prevalence of 0.33% although other groups that question this figure estimate the true prevalence to be at least twice as high.

Multiple coinfections

There were suggestions that people with HCV who became infected with hepatitis A were at risk of fulminant hepatitis and possible death (Vento et al 1998). However a larger follow-up study showed no deaths from acute hepatitis A infection in those with HCV (Mele et al. 1998). None of the people in the studies had HIV as well so beyond highlighting the importance of being vaccinated it is difficult to give any recommendations.

For people with HIV and hepatitis C contracting hepatitis B is obviously not a good thing. In practice there has not been much evidence to suggest that the illness is worse or the chance of liver failure increases in people who already have HCV. Little research has focussed on people with multiple hepatitis viruses and no recommendations have come from the studies that have been done.

It seems that other factors such as alcohol consumption have a greater influence over the chances of developing liver cancer. Therefore the prognosis for patients with multiple viruses is probably worse, but maybe not dramatically so.

Conclusion

Hepatitis C is a complex condition and linked to a number of other medical disorders, some of which are serious. Because the picture is still emerging it is not yet possible to give a full list of symptoms, their likelihood of appearance in individual persons, the possible factors influencing their occurrence and the overall impact of HCV infection on quality of life and longevity. HIV co-infection complicates this even more.