Hepatitis C (HCV) is a single-stranded RNA virus. In 1990, the partial genetic sequence of the virus was reported and the first diagnostic test became available to detect antibodies to the virus in blood. These antibodies are not protective against the virus but are a helpful marker of infection in that most people with HCV antibodies are actively infected and contagious. HCV is responsible for most cases of what was previously called "Non-A, Non-B Hepatitis".

Risk factors for Transmission

• Blood Exposure, Needle Stick Injury or Transfusion
• Illegal Drug Use, Including "snorting"
• Tattoos or Body Piercing
• Sexually Active with Multiple Partners
• Transmission of HCV can occur by blood transfusions (now very rare), needle
• Stick injuries to health care workers, and drug abuse through sharing of infected needles (most common).

One of the mysteries surrounding HCV is that the mode of transmission is not identified in more than 20% of cases. The spouses of infected people are at slightly increased risk although the mechanism of transmission to spouses is not known. Transmission to spouses during intercourse is so rare that condom use is usually NOT advised for a patient who is in a long-term relationship with one partner. Certainly HCV is in blood, and sexual behavior should be considered dangerous where blood may be spread such as when there is a cut or sore in the genital areas.

Acute Hepatitis C develops approximately 6 to 10 weeks after infection. Patients may experience no symptoms or merely a mild flu-like illness lasting a few days or weeks and usually without jaundice (yellow skin and eyes). Usually, liver blood tests are not measured and Hepatitis C is not suspected or diagnosed until years or decades later.

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HIV and Hepatitis C

The last several years, as the overall prognosis of maintained life with aggressive antiviral therapy with respect to HIV has become a reality, issues surrounding other chronic confections have taken on new interests with the HIV patient. Specific to this is the issue of co-infection of the HIV patient with hepatitis C. There is some data to suggest that patient who in fact have HIV and who are co- infected with hepatitis C may have a particularly poor prognosis with respect to liver disease caused by hepatitis C. Hence, there is increasing interest in the protocol for treating patients with HIV and hepatitis C, with eradication being its end-point. Essentially, hepatitis C and HIV are very similar viruses, in that they are both single-strand RNA viruses. They both have worldwide distribution. With respect to hepatitis C, there are six general genotypes that are well described in the literature. In addition, within genotypes there are sub variations of genetic makeup, known as quasi-species. In the majority of hepatitis C patients, infection causes chronic infection of the liver, of which most infections are sub clinical, with respect to symptomatology, until at a later point when end-stage liver disease develops secondary to cirrhosis. The rate of viral production is very high for both HIV and hepatitis C.

Globally, approximately 30 to 35 million people are infected with HIV, and about 170 million people are thought to be infected with hepatitis C, almost six times as many as with HIV. Although hepatitis C has not historically received the recognition that HIV has, both viruses are significant public health problems worldwide, and of recent, there has been increased recognition in the United States of the importance of hepatitis C. This is due to a recent announcement made by the CDC regarding attempts to contact blood recipients from prior to 1990 with respect to the possibility that they may have been infected with the hepatitis C, and also due to multiple targeted media campaigns, sponsored by both the pharmaceutical industry and by researchers and health care organizations.

Hepatitis C, hepatitis B and HIV may be transmitted by percutaneous sharp exposure, but hepatitis B and hepatitis C are transmitted much more readily by this route. Hepatitis B and hepatitis C are found with a high prevalence among HIV drug abusers, though likelihood of infection seems to have increased with time with respect to IV drug abuse. It is interesting that several studies suggest that at the initiation of an IV drug use habit, infection by either hepatitis C or hepatitis B tends to occur in the first few months of addiction. In a study published by Thomas et al. in the Journal of Infectious Disease in 1996, there is some evidence to suggest that HIV infections may increase the risk of transmission of hepatitis C. As CD-4 counts are shown to decline, hepatitis C viral loads tend to increase dramatically. Perinatal transmission of HIV and hepatitis C virus is greater in co- infected women than in those who have either HIV or hepatitis C virus infection alone. In a study done by Zanetti et.al.(Lancet. 1995), these researchers compared the likelihood of perinatal transmission of HCV between women who either were or were not co- infected with HIV. Hepatitis C virus was transmitted to 36% of infants whose mothers were HIV positive but to none of the infants whose mothers were HIV negative. Similarly, in a study by Hershow et al. in the Journal of Infectious Disease in 1997, HIV-infected women were more likely to transmit the virus perinatally if they were also infected with hepatitis C virus.

With respect to chronic hepatitis C infection in general, this tends to be an organ-specific disease in that it causes primarily chronic hepatitis in the majority who are infected with the virus. In a minority of these patients, chronic infection may lead to cirrhosis, and certainly in those patients with cirrhosis, there is an increased risk of hepatocellular carcinoma. In addition to organ-specific disease of the liver, hepatitis C has been clearly linked to the development of mixed cryoglobulinemia, membranoproliferative glomerulonephritis, and porphyria cutanea tarda (PCT). With respect to PCT, recent studies have suggested that approximately 85% of the patients who have PCT have hepatitis C virus, though the precise relationship between hepatitis C infection and PCT is not exactly known. In general, most patients who get hepatitis C will develop chronic hepatitis C in that approximately 80% of the patients who are infected with the virus go on to develop some form of chronic infection of their livers. Of those patients with chronic liver disease, approximately 20% to 30% will go on to develop cirrhosis, and approximately 80% will have some form of stable chronic disease, causing chronic inflammation with mild-to-moderate fibrosis.

It is the patients who develop cirrhosis that are of the greatest concern, since these patients have an increased risk of hepatocellular carcinoma and may go onto early decompensated liver disease resulting in death if not provided hepatic transplantation. In fact today, the leading indication for liver transplantation in the United States is hepatitis C. It has been estimated that there are approximately 8000 to 10,000 deaths per year attributed to hepatitis C in the United States today. It has been suggested in some modeling by the CDC that medical costs for hepatitis C cost well over 600 million dollars annually and that these costs will only increase over the next several years as patients become more advanced with respect to their liver disease and transplantation is required. It has been estimated that approximately 1.8% of the population has hepatitis C in the United, States or approximately 3.9 million people. ( In a city of Jacksonville’s size of 1.1 million people, that would mean approximately 19,800 are presently infected.) Of these 3.9 million infected Americans, 2.7 are considered chronically infected, and most of these infected patients today are between the ages of 30 and 50 years of age. In addition, with respect to active new cases, the actual epidemic has already happened. In fact, the incidence of new infection has declined in the last several years, especially in the last half decade. This probably is the result of the ability to now mass screen the blood supply, especially in blood components being used for transfusion purposes. In addition, all patients undergoing insurance examinations, most executive physical examinations, and all blood donors are tested for hepatitis C. Hence, this has dramatically increased the awareness of who is already infected with this disease. In addition, there have been several national campaigns, as described above, increasing the awareness of this infection, highlighting those who are at greatest risk to have this infection, and causing a substantial increase in the number of patients tested by their primary care physicians in the last several years.

It has been suggested in a study by Dr. Gary Davis, presented at the 49th Annual Meeting of the American Association for the Study of Liver Disease in 1998, that the percentage of hepatitis C virus positive patients with cirrhosis will increase from approximately 15.6% in 1998 to approximately 28.9% by 2018. Of these, the percentage with hepatic decomposition will increase dramatically as will the number with hepatocellular carcinoma. In addition, liver-related deaths will increase threefold. Hence, the issue of hepatitis C is real. In general, if one were to develop an algorithm in one’s mind about the outcome of hepatitis C and were to take 100 patients affected acutely with hepatitis C, approximately 85 would go on to develop some form of chronic liver disease. Of those, approximately 17, or 20%, would develop cirrhosis. Of those with cirrhosis, approximately 25% would go on to have decomposition with early mortality.

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Hepatitis C Disease Pathogenesis

With respect to the pathogenesis of hepatitis C infection, this is not completely understood. Infection of hepatocytes by hepatitis C results in cell death, probably as a result of hepatitis C-induced apoptosis. The cell-mediated immune system may also play a role in the destruction of hepatocytes, especially as a result of the activity of CD8 and T-helper cells. In addition, the production of various cytokines in response to hepatitis C virus infection increases the activity of hepatic stellate cells, the principal producers of the extra cellular matrix. This activation may occur directly in response to exposure to factors such as Interferon, or it may be an indirect response to the release of TGF-beta from Kupffer's cells.

Increased activation of hepatic stellate cells results in an increased production of extra cellular matrix, hence causing new fibrosis. There still are factors that influence the progression of hepatitis C virus infection. These include viral load, genotype, and the presence of quasi-species and mode of transmission. In addition, host-related issues such as age, race, gender and immune response also play a role. In addition, co- infection with HIV and hepatitis B, the consumption of alcohol and less geography and smoking may also play as factors influencing the progression of hepatitis C virus infection.

With respect to HIV, the progression of fibrosis among the patients with hepatitis C virus infection is accelerated by co- infection with HIV. A study by Benhamou et al. in Hepatology in 1999, found that an increase in hepatitis C virus-related fibrosis over time was significantly greater among patients who were HIV positive than among HIV-negative control. The two groups were matched with regard to several clinical factors, including age, sex, and alcohol consumption. These findings suggest that hepatitis C infection behaves as an opportunistic infection with respect to HIV.

In another study Darby et. al. published in Lancet in 1997, the study looked at 4,865 men and boys in the United Kingdom who had had hemophilia and who were treated with blood products having a high probability of contamination with hepatitis C virus between 1969 and 1985. Compared with the general United Kingdom population, patients with hepatitis C virus infection have a 16.7 fold increase in the likelihood of dying from liver-related causes. However, the incidence of liver-related mortality among the co-infected patients was increased by a factor of nearly 100, approximately seven times that of patients who are HIV negative.

In another study published in the Journal of Infectious Disease in 1999 by Lesens et al, the effects of HIV infection on the progression of liver disease due to hepatitis C was examined in the cohort of patients with hemophilia. A total of 154 hepatitis C virus-positive patients were studied. 81 patients were also infected with HIV. More than 25% of patients with progressive liver disease were co- infected with HCV and HIV while only approximately 5% were infected with the hepatitis C virus alone. Risk of occurrence of progressive liver disease in co-infected patients was 7.4. Progressive liver disease developed, with duration of 17.2 years. The development of progressive liver disease in these patients was more likely among those with severe AIDS-defining immunodeficiency’s than among patients without AIDS-defining immunodeficiency. 73% of patients who had AIDS survived for 3.2 years after experiencing progressive liver disease.

Overall, about 40% of patients with HIV infection are co- infected with hepatitis C virus. The number of co-infected patients seen by physicians will vary with the patient population served. The greatest number of co-infected patients are found in settings where there are large numbers of HIV drug abusers. About 70% of patients being treated for HIV are on protease inhibitors. A significant number are also infected with hepatitis C virus, thus increasing the risk for progression of liver disease. Even in the absence of co- infection with hepatitis C virus, it is common for patients with HIV to have liver function abnormalities. Protease inhibitors that are currently used for the treatment of HIV do not affect the hepatitis C virus. There is no sufficient homology between the two viruses. The degree of control of HIV replication obtained using HAART does not affect hepatitis C viral levels. Initiation of HAART can produce transient elevation of ALT, AST and hepatitis C virus levels. Much of the hepatotoxicity that is associated with nucleoside analogue drugs is caused by damage to mitochondrial DNA. Replication of mitochondrial and nuclear DNA are regulated by different enzymes. Several nucleoside analogues, most notably FIAU, are inhibitors of DNA polymerase gamma, the mitochondrial DNA polymerase. The disruption of mitochondrial metabolism causes an accumulation of triglycerides and pyruvates, which in turn causes the development of lactic acidosis. The drugs, D4T, DDC, and DDI are the most likely to cause lactic acidosis, although these effects can be produced by any nucleoside analogue.

Underlying liver disease, such as hepatitis B or hepatitis C, can also impair mitochondrial function, and thus patients who are infected with hepatitis B virus or hepatitis C virus are at risk for added hepatotoxic effects.

In the study published in JAMA this year by Sulkowski, 282 patients were evaluated who were being treated with new anti-viral treatments were followed prospectively for the appearance of hepatotoxicity assessed by performing serial ALT determinations during a period of six months. The primary purpose of this study was to determine whether the risk of hepatotoxicity is comparable for all anti-viral treatment regimens and determines the impact of hepatitis C virus co- infection on anti-viral drug-associated hepatotoxicity. Of drug studies, ritonavir was associated with a higher incidence of severe hepatotoxicity than any other treatment regimen examined. Most patients (88%) with hepatitis B virus infection did not develop severe hepatotoxicity. Among patients prescribed a treatment regiment that did not include ritonavir, hepatitis C virus infection increased the risk of hepatotoxicity by 3.7-fold. Among patients who received ritonavir, there was no difference in hepatotoxicity between patients with hepatitis C virus positive and hepatitis C virus negative.

Based on this study, a following approach has been suggested in the management of HAART-associated hepatotoxicity. For mild to moderate increases in serum ALT or AST, the patient should be monitored and observed closely without change in therapy until the patient becomes symptomatic. With severe elevation, 3.5-fold increases, all anti-viral medications should be stopped. To continue the use of only one or two the anti-viral medications could lead to increased resistance to therapy. The physician should also rule out alternative possibilities, such as hepatitis A and hepatitis B. Liver enzymes will usually decrease over a period of five to ten weeks with the cessation of anti-viral therapy. When re-starting HIV medication treatment, consider a non-ritonavir-based regimen.

With respect to patients who have HIV, with respect to hepatitis C, screening for hepatitis C should be mandatory. In addition, patients who have co- infection with hepatitis C should not drink alcohol. There is clear evidence that alcohol consumption has synergistic effects on the viral activity of hepatitis C with respect to its ability to induce progressive liver damage. Anti-viral medications are well known to cause liver disease as described above. An aggressive HIV therapy should not be withheld from patients who have hepatitis C, but hepatic effects should be clearly monitored.

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Treatment for Hepatitis C

As described above, with the increasing effectiveness of chronic therapy for patients with HIV and the successful ability to maintain these patients for indefinite periods of time, the clinical and relevant issues of hepatitis C co- infection have become real. Hence, treatment is now clearly indicated. There are patients, though, for which probably therapy is more indicated than in others.

In general, all patients with hepatitis C should have a liver biopsy. This will serve as a good baseline with respect to the effects of hepatitis C that has occurred to the liver. Patients, who have very mild disease, may very well not have aggressive disease, especially if they have had the virus for some time. On the other hand, patients who have rather advanced fibrosis and inflammation probably have an advanced form of the disease, either solely as a result of the hepatitis C or secondary to co-factors such as HIV or long-term alcohol consumption. There is increasing evidence that the use of long-term maintenance therapy in patients who have hepatitis C with advance fibrosis may retard for a period of time the progression of the liver to full decompensation and the need for transplantation, and in fact there are ongoing, long-term clinical trials to prove the efficacy of long-term administration of Interferon in such patients irrespective of its ability to clear the virus.

At general, in patients who are HIV negative who have hepatitis C, the first primary goal of therapy with pharmacotherapy is to eradicate the virus. Unfortunately, this goal is often not met. But as described above, the mere presence of some form of long-term pharmacotherapy for the eradication of hepatitis C, even when met with failure with respect to eradication, may have some long-term benefits with respect to retarding the virus with its effect of fibrosis and subsequent cirrhosis.

The present gold standard for hepatitis C therapy in patients who are not HIV positive includes the use of two drugs known as Interferon and ribavirin. Initially, several years prior, the sole therapy for hepatitis C was monotherapy with Interferon, given for approximately 6 months’ time. With gradual accumulation of data, recommendations from the national institute of health suggested lengthening this treatment up to 12 to 18 months. Approximately 3 years ago, the introduction of ribavirin as a form of synergistic pharmacotherapy with Interferon was suggested and eradication rates were suggested to be significantly improved with this form of combination therapy. In general, Interferon therapy alone for approximately 6 months probably only causes approximately 6% to 8% sustained response. With combination of Interferon and ribavirin, we can see increased sustained response of between 30% and 40%(McHutchison et al. NEJM 1998). This response can be measurably increased by lengthening the duration of Interferon and ribavirin therapy such that in most cases, we are treating now patients for approximately 48 weeks. Patients who seem to respond the best with respect to Interferon- and ribavirin-based therapy are those with genotype II and III. Unfortunately, the majority of the patients we will see in the United States have genotype Ia and Ib, which seems to be the least effective with conventional Interferon and ribavirin therapy. In addition, pretreatment viral loads of less than 2 million copies per cubic centimeter have been suggested to have a better prognosis with respect to long-term Interferon and ribavirin therapy. In addition, the female gender or an age less than 40 has also been suggested to be associated with increased response to Interferon and ribavirin therapy.

Cirrhotics in general do not do well with respect to Interferon and ribavirin therapy, but on the other hand, as already described, there is increasing evidence that such patients should not be discounted from therapy, as long-term Interferon therapy may improve these specific patients with respect to outcomes and the need for early transplantation. However, this issue still awaits long-term outcome studies which are presently being undertaken. Historically, the gold standard for consideration for Interferon therapy with ribavirin in patients with hepatitis C have been in those patients who have elevations of their ALT. Hepatitis C is a unique viral hepatitis in that you may see fluctuations from normal to high levels of ALT through the course of serial blood draws. This is not the case, necessarily, with hepatitis B or other forms of chronic hepatitis. Hence, one single normal ALT does not exclude the presence of chronic hepatitis. Early clinical studies suggested that in patients, though, who have persistently normal ALTs and who are treated with Interferon, there may be actually no improvement with respect to their chronic hepatitis C and potential worsening of their disease, though this issue is an area of intense investigation, with a large multi-center study presently being undertaken by Dr. Bruce Bacon of St. Louis University. In this study, he is investigating in the first large multi-center study the effectiveness of treating patients who have persistently normal ALTs with Interferon therapy. At present, however, the gold standard is to not treat patients who have normal ALTs with Interferon. This may be somewhat troublesome in that, if you biopsy many patients who have normal ALTs persistently, their biopsies may in fact show evidence of chronic hepatitis. As already stated above, the present standard of care is to not treat such patients with persistently normal ALTs.

In general, Interferon is well tolerated. Early on in its use, there was tremendous concern about the potential relationship between Interferon and underlying depression and other psychiatric disorders. In fact, we have found that with close monitoring, even in patients with known documented psychiatric history, a full 48 weeks of pharmacotherapy can be achieved. In fact, we have advocated the initiation of patients who are going to be treated with Interferon therapy with some kind of antidepressant; specifically, we have used SSRIs as the principal form of antidepressant in these patients, usually initiating therapy approximately 2 to 3 weeks prior to the start of Interferon-based therapy. Interferon may cause the clinical manifestations of underlying thyroid disease. In addition, it has been reported to manifest underlying diabetes mellitus. In addition, it may have several hematological disturbances. Ribavirin, though, has been more of a concern secondary to its effect of hemolysis. Hence, any patient on ribavirin needs to be closely monitored with serial CBCs, which we usually recommend every other work for at least the first 3 months of therapy. If hemolysis occurs, we recommend dose reduction of the ribavirin to an appropriate level, where hemoglobin levels can be maintained in a safe therapeutic range. There are early studies looking at the effects of antioxidants, specifically vitamin E, in preventing this effect of hemolysis, though data with respect to vitamin E is still pending. In addition, there is some data that erythropoietin may help with respect to off setting this hemolysis, though again this is certainly by no means the standard of care at present. Other areas of active research include the use of IL-10 along with interferon therapy, since IL-10 is known to have anti-fibrosis activity. There has been some work looking at the use of IL-2 along with interferon, in addition, there are studies looking at different dosing strategies with interferon.

In general, for all patients who we treat with hepatitis C, either HIV or not HIV infected, we recommend drawing a baseline CBC, hepatitis-C PCR RNA with Genotype, electrolytes, liver function studies, and TSH prior to the initiation of therapy. In addition all patients with Hepatitis C who do not have immunity to either Hepatitis A and or B we recommend vaccination as per the CDC. With the initiation of therapy thereafter, every 2 weeks we repeat the CBC, liver function studies and electrolytes, and if we see stabilization of the CBC within acceptable parameters, then we can lengthen the intervals between lab draws to every 4 weeks after the first 3 months of therapy. Clearly, amongst clinicians there are variations in these schedules of blood draws, but we have found this protocol to be the most useful with respect to picking up early hematological concerns in relation to pharmacotherapy. In addition, I have employed a standard of seeing these patients physically every 2 weeks during the first 3 months of therapy since the effects of Interferon with respect to psychological ,biochemical, and hematological concerns seems to be most pronounced during the initiation of therapy. Thereafter, if patients seem to be doing well, every month seems to be a reasonable interval to meet with the patient and review their labs. We also recommend a full physical examination on each visit, with careful attention with respect to any clinical complaint that the patient may be having.

Lastly, we have strongly encouraged the use of outside support groups for patients considering therapy or who are on therapy. The support group seems to help the patient find fellowship with other sufferers. More importantly, it allows them a standard to which they can feel comfortable with respect to the magnitude of impact that the therapy has on their daily lives. We have such a support group here in Jacksonville, and it has been active for the last 3 years.

In conclusion, hepatitis C is a real infection of concern, and especially now that our HIV patients are living and doing well with antiviral therapy, with the goal that we will eventually find some form of therapy to cure them of their HIV, it is only appropriate that we treat them for their hepatitis C virus.

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