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Pathogenesis, Viral Dynamics, & Immunologic Response of Hepatitis C Virus

July 9-14, 2000

Most people infected with hepatitis C virus (HCV) do not have any acute signs or symptoms of hepatitis. They usually remain unaware that they have been infected during the first 10-20 years, unless they have a blood test. They will usually be found to have some elevations of liver enzymes in their blood, as a result of leakage of these enzymes from damaged or dying liver cells. Specific blood tests can determine the presence of antibodies to HCV, or measure the blood level of HCV RNA, also know as viral load, by polymerase chain reaction (PCR). HCV RNA is detectable within a few days after infection, and antibodies usually become detectable within 45-90 days (Seeff 1995).

The precise mechanisms by which HCV infection causes liver damage are not known; however, there is strong evidence that a person's own immunologic response to HCV contributes significantly to this process. The process of inflammatory changes seen in the liver over time results in the formation of scar tissue -- fibrosis -- that leads to cirrhosis. Cirrhosis -- extensive scarring of or fibrotic tissue replacement in the normal liver -- is responsible for the life-threatening complications of HCV and hepatocellular carcinoma (liver cancer). Carlo Ferrari and colleagues write:

The final outcome of infections by viruses that cause chronic diseases is believed to depend mostly upon the rate of replication of the infecting virus and the capacity of the immune system to mount rapid, multispecific and efficient virus-specific responses to inhibit infection before the virus can devise strategies to evade immune surveillance. (Ferrari 1999)

HCV is a single-stranded RNA virus which does not integrate into the host's genetic material. HCV must constantly replicate to maintain its presence in the human body and is very efficient at replicating inside of human cells.


HCV Replication and Kinetics

HCV infection persists in 70-85% of people infected, despite evidence of "readily detectable, multispecific, humoral and cellular immune response directed against all the viral structural and nonstructural proteins" (Chang 1998). HCV replication has been detected in hepatocytes (liver cells) and in peripheral blood lymphocytes, but not in immunologically protected sites, such as the testes and brain (Chang 1998).

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Laskus and colleagues searched for sites of HCV replication outside of the liver in HCV/HIV coinfected people (Laskus 1998). They found evidence for HCV replication in the lymph nodes, pancreas, adrenal glands, thyroid, bone marrow, and spleen in an autopsy study of eight people who were severely immunocompromised at the time of death. The amount of HCV produced from these sites appeared to be relatively low. The clinical significance of extrahepatic HCV is not fully understood, and it is difficult to definitively determine the presence of replication in the absence of an in vivo model. In a recent publication, Laskus documented evidence of HCV replication in peripheral blood cells (monocytes/macrophages, and T and B cells) in HCV/HIV coinfected patients. He suggests that HCV may replicate in the same cells infected with HIV and that there may be direct interactions between the two viruses (Laskus 2000). These data, however, have yet to be confirmed.

HCV production on a daily basis can be very high. HCV production can be as high as 1 x 1012 virions (one trillion) per day (Neumann 1998). Average HCV RNA levels (viral load) in people coinfected with HIV have been reported to be as high as 16.8 million copies per milliliter (mL) (Mika 1999). The half-life of an HCV virus is about 2.7 days (Neumann 1998).

Thomas and colleagues studied HCV RNA levels in 969 HCV-infected people, 468 with HIV and 501 without (Thomas 2000). They found that factors associated with lower average HCV RNA levels in the HIV-negative group included younger age, ongoing hepatitis B infection, and the absence of needle sharing. In the HCV/HIV coinfected group, no differences in HCV RNA levels were correlated with age, race, gender, or alcohol or drug use:


Mean HCV RNA Level in Patients with and without HIV

GroupMean HCVRNA Level
Total(N = 969)9.3 million copies/mL
HIV-negative(N = 501)6.73 million copies/mL
HIV-positive(N = 468)7.19 million copies/mL
(Thomas 2000)


When interferon alfa (IFN) therapy is given to people with HCV infection, there is a two-phase decay. There is an initial rapid decrease in HCV RNA, then a secondary, slower decay, or decrease. The initial decay, about a 1.5 log decrease in HCV RNA seen during the first 48 hours, is thought to represent the blockage of HCV production by IFN. The second, slower phase of decay is thought to represent the death of HCV-infected hepatocytes, or liver cells (Neumann 1998; Perelson 1999a; Yasui 1998).

In HIV/HCV coinfected individuals, HCV RNA levels are observed to increase after the second day of IFN treatment even though there was a rapid decrease the first day. One interpretation of this observation is that while HIV coinfection does not interfere with IFN's ability to reduce HCV production, HIV infection may interfere with the eradication of infected hepatocytes (Mika 1999). This hypothesis, however, is very speculative.


Comparative Viral Kinetics


HIVHBVHCV
Half-life< 6 Hours24 Hours3 Hours
Daily viral production> 10 10> 10 11> 10 12
Perelson 1999a; Ramratnam 1999)


Perelson noted that while HCV does not cause clinically significant liver disease for decades, it is still a very dynamic process, with tremendous daily viral production, in most HCV-infected people.

Daily dosing of IFN, or the use of experimental IFNs with longer half-lives, such as pegylated-interferons, has been suggested as a way to increase the efficacy of therapy for HCV, due to the very large number of virions produced each day and the rebound in production which occurs on day two after IFN therapy (Zeuzem 1999). (See "HCV Treatments" chapter.) The changes in HCV RNA levels after the first four weeks correlate with the chance of obtaining a sustained response to therapy (Walsh 1998). Thus, kinetics studies are not only of academic interest, but may help design more rational therapy and predict earlier who might benefit from continued therapy.


Immune Responses to HCV Infection

Studies have shown that neutralizing antibodies are produced during HCV infection, but they do not appear to be protective against re-infection in humans or in chimpanzees (Ferrari 1999). The more critical determinant of the outcome of HCV infection seems to be the cell-mediated immune response, or the T-cell (CD4) response. People who are able to spontaneously clear HCV from their body have evidence of strong T-cell responses. Conversely, people who are chronically infected with HCV do not appear to either mount a strong T-cell response early after HCV infection, or maintain an initial strong T-cell response to HCV antigens (Gerlach 1999). In Gerlach's study, the 20 people (52.6%) out of 38 studied who cleared HCV infection all had a strong and sustained antiviral T-cell response to HCV, while the people who became chronically infected either showed no initial T-cell response (12, 31.6%) or did not maintain an initial strong antiviral T-cell response (6, 15.8%).

Over time, however, in most people chronically infected with HCV, T-cell responses increase but are not able to clear HCV. Ferrari and colleagues write that:

More information about the immune events taking place within the inflamed liver is required to draw a more reliable picture of HCV pathogenesis and to create the ground for more effective strategies of prevention and treatment of HCV infection. (Ferrari 1999)

Another limitation of current research is the lack of necessary cell culture systems and animal models to study the many complex factors involved in the immunologic responses to HCV infection (Cerny 1999).


Possible Strategies for a Virus to Escape Immune Elimination

  1. Decrease its visibility to the immune system.
  2. Decrease the effectiveness of antiviral cytokines.
  3. Increase the resistance of infected cells to CTL-mediated killing.
  4. Infect immunologically privileged sites.
  5. Induce immunologic tolerance.
  6. Immunologic evasion.
    (Cerny 1999)

Generally neither HCV RNA levels nor alanine aminotransferase (ALT) levels (liver enzyme levels) correlate very well with the extent of liver damage seen on biopsy. Gretch and colleagues, however, have reported that replication of HCV in human liver tissue shows a significant correlation with the severity of HCV infection. They reported a very strong correlation with the percentage of human liver tissues cells infected with HCV in vitro, and the degree of hepatic inflammation (Gretch 1999). They suggest that the amount of damage to the liver may be a factor of the process of HCV replication, not merely the presence of HCV in the liver.


Arguments Supporting the Relevance of Immune-mediated Liver Cell Damage in HCV Infection

  1. In primary HCV infection, liver cell damage correlates with the development of the host immune response -- not with infection and HCV viral replication.
  2. Chronic HCV replication can occur without significant liver cell damage.
  3. HCV infection of liver cells does not appear to kill the infected liver cells.
  4. Immunosuppression of people with HCV infection results in transient improvement in liver function tests, despite a surge in HCV RNA levels.
  5. Liver cell damage is associated with an inflammatory infiltrate, and liver-infiltrating HCV immune cells associated with areas of liver damage suggest a causative role.
    (Cerny 1999)


HCV Eradication?

While HCV is an RNA virus, it is not a retrovirus; therefore, HCV does not incorporate its genetic code into the host cell's DNA. So if all infected liver cells, or hepatocytes, and any other cells in the body which are infected with HCV die -- and there are no free HCV virions around to infect new cells-then the person will no longer be infected with HCV (i.e., the infection will be eradicated). Some investigators believe that most people who remain without detectable HCV RNA six months after therapy have achieved eradication (i.e., they are cured). (See "HCV Treatments" chapter.) Approximately 15% of people acutely infected with HCV are able to achieve life-long eradication of HCV from their body by their immune response. (See "HCV Natural History" chapter.) Whether people are in fact cured will require longer follow-up; however, there is an important implication to achieving eradication. People can be re-infected with HCV after they have had the initial HCV infection eradicated; there is no life-long HCV immunity (Farci 1992).


Extrahepatic Manifestations of HCV

While the primary site of clinical infection with HCV is the liver, a significant number of people develop disease symptoms at sites other than the liver, referred to as extrahepatic manifestations of chronic HCV infection. A recent report reviewed sites of HCV infection in 1,604 patients infected with HCV; it found that 74% of people had at least one extrahepatic manifestation of HCV infection (Cacoub 1999). The most common manifestations were:
  • Arthralgia (joint pains)
  • Paresthesia (nerve sensation abnormalities)
  • Myalgias (muscle pain)
  • Pruritus (itching)
  • Sicca syndrome (dry eyes, skin, and mouth)

The report also noted some laboratory abnormalities such as cryoglobulinemia (increase in a certain type of "cold" antibody in the blood), antinuclear antibodies, low thyroxine (thyroid enzyme) levels, and anti-smooth-muscle antibodies. A multivariate analysis demonstrated that the following factors were associated with an increased incidence of extrahepatic manifestations:

  • Age
  • Female gender
  • Extensive liver fibrosis (scarring)

Another study reported that 38% (122/321) of people with HCV infection had at least one extrahepatic manifestation, including joint pains (19%), skin changes (17%), dry mucous membranes (12%), and sensory nerve changes (9%). Thus, the most common symptoms involved the joints and skin. HCV/HIV coinfection was associated with an increased incidence of low platelet counts (thrombocytopenia) and autoantibodies (antibodies against body tissues) (Cacoub 2000).

All of these symptoms and laboratory abnormalities are typically seen in people with autoimmune diseases, or people with diseases that are the result of their own immune system attacking components of their own body. This observation provides additional support to the belief that much of the damage observed due to HCV infection is actually a result of an overactive immune system, or an immune system that is mistakenly attacking components in the body as it attempts to attack HCV.

The pathogenesis, viral dynamics, and immunologic response of HCV remain incompletely understood. Reliable and efficient cell culture systems and a small-animal model are needed to better understand these areas. It is hoped that further advancement in this field will lead to novel therapeutic agents to treat and cure patients with HCV.


References

Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. Arthritis Rheum 42:2204-12, 1999.
Cacoub P, Renou C, Rosenthal E, et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Medicine (Baltimore) 79:47-56, 2000.
Cerny A, Chisari FV. Pathogenesis of chronic hepatitis C: immunologic features of hepatic injury and viral persistence. Hepatology 30:595-601, 1999.
Chang K. The mechanisms of chronicity in hepatitis C virus infection. Gastroenterology 115: 1015-17, 1998.
Farci P, Alter HJ, Govindarajan S, et al. Lack of protective immunity against reinfection with hepatitis C virus. Science 258:135-40, 1992.
Ferrari C, Urbani S, Penna A, et al. Immunopathogenesis of hepatitis C virus infection. J Hepatol 31:31S-38S, 1999.
Gerlach JT, Diepolder HM, Jung MC, et al. Recurrence of hepatitis C virus after loss of virus-specific CD4+ T cell response in acute hepatitis C. Gastroenterology 117:933-41, 1999.
Gretch DR, Chang M, Williams O, et al. Active replication of HCV in human liver tissue shows a significant correlation with severity of hepatitis C In vivo [abstract]. Hepatology 30:353A, 1999.
Laskus T, Radkowski M, Piasek A, et al. Hepatitis C Virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis 181:442-8, 2000.
Laskus T, Radkowski M, Wang LF, et al. Search for hepatitis C extrahepatic replication sites in patients with acquired immunodeficiency syndrome: specific detection of negative strand viral RNA in various tissues. Hepatology 28:1398-1401, 1998.
Manns MP, Rambusch EG. Autoimmunity and extrahepatic manifestations in hepatitis C virus infection. J Hepatol 31:39S-42S, 1999.
Mika BP, McCarthy ME, Layden TJ, et al. HIV/HCV co-infected patients experience HCV viral rebound after the second day of IFN treatment [abstract]. Hepatology 30:195A, 1999.
Min A, Jones J, Esposito S, et al. Early hepatitis C viral RNA decline during therapy with interferon alfa-2b and ribavirin in patients with chronic hepatitis C without sustained response to prior interferon [abstract]. Hepatology 28:A29, 1998.
Munoz S, Suvannasankha A, DiGregorio K, et al. Retreatment with ribavirin and interferon alpha 2b of relapsers and nonresponders to monotherapy [abstract]. Hepatology 28:A28, 1998.
Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science 282:103-7, 1998.
Perelson AS. HCV dynamics: a guide to patient management [slide lecture & syllabus]. AASLD, Postgraduate Course, Dallas, 5 November 1999.
Perelson AS. Viral kinetics and mathematical models. Am J Med 107:49S-52S, 1999.
Ramratnam B, Bonhoeffer S, Binley J, et al. Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis. Lancet 354:1782-85, 1999.
Seeff LB. Hepatitis C. Semin Liver Dis 15:1, 1995.
Thomas DL, Astemborski J, Vlahov D, et al. Determinants of the quantity of hepatitis C virus RNA. J of Infect Dis 181:844-51, 2000.
Vucelic B, Ostojic A, Hrstje B, et al. Viral kinetic study of induction dosing with interferon alpha and ribavirin in the treatment of chronic hepatitis C [abstract]. Hepatology 28:A32, 1998.
Walsh KM, Good T, Cameron S, et al. Viral kinetics can predict early response to alpha-interferon in chronic hepatitis C. Liver 18:191-5, 1998.
Yasui K, Okanoue T, Murakami Y, et al. Dynamics of hepatitis C viremia following interferon-alpha administration. J Infect Dis 177:1475-9, 1998.
Zeuzem S. Clinical implications of hepatitis C viral kinetics. J Hepatol 31:61S-4S, 1999.



  
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This article was provided by Treatment Action Group. It is a part of the publication The Hepatitis Report.
 

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