Written for NATAP by Andrew Talal, M.D., M.P.H., Assistant Professor of Medicine, and Ira Jacobson, M.D., Vincent Astor Distinguished Professor of Clinical Medicine, Director of GI and Hepatology, both at Weill Medical College of Cornell University
In the past twenty years, two newly described human viruses, the hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) (one infecting the liver and the other critically weakening the immune system) have dramatically awakened our understanding of just how fragile is the relationship between humankind and pathogenic microorganisms. These two viruses are similar in many respects. Both viruses have a single-stranded RNA genome, they both have very high levels of viral replication, they both cause chronic subclinical infection that can persist for many years, and they share similar routes of transmission. However, HIV and HCV are also different in many respects. One of the most important differences between these two viruses is that HCV does not have a nuclear phase during its replication cycle and it does not integrate into the host genome unlike HIV. Nuclear phase means that the virus goes into the nucleus of the cell. Both HBV and HIV have a portion of the life cycle that occurs in the nucleus, while HCV does not. HIV can integrate into the host genome and HBV can survive as a closed circular coil (referred to as "ccc"). At least, theoretically it should be possible to eradicate HCV more easily than HBV or HIV. Based on this fact, HCV eradication from the body should be much easier to accomplish than eradication of HIV. With the recent introduction of a new formulation of interferon conjugated to polyethylene glycol, pegylated interferon, many HCV-infected individuals will have the opportunity to be "cured" from HCV infection.
This review will discuss the epidemiology, management and treatment of HCV as well as the differences between HIV and HCV. Hepatotoxicity secondary to antiretroviral agents, which is clearly an increasing problem in the treatment of HIV-infected individuals, will not be covered in this review.
Hepatitis C virus (HCV), a member of the Flaviviridae family (1), consists of at least 6 genotypes and more than 50 subtypes. Genotype 1 is the most common in the United States and genotypes 2 and 3 are the most common in Europe and Asia. An estimated 3.8 million individuals in the United States, 1.8% of the population, have been exposed to HCV, and 2.7 million of these individuals have detectable HCV RNA indicating chronic viral infection (2). The virus causes approximately 10,000 deaths each year (3). HCV has infected an estimated 170 million individuals worldwide and the virus is the leading cause of liver transplantation (4). In comparison, HIV has an estimated prevalence of 800,000-900,000 in the United States (5). Recent studies suggest that, in the era of potent antiretroviral therapy, the number of deaths due to liver disease in HIV-1-infected individuals has been increasing. In a cohort of ~4,000 individuals, liver disease was the primary cause of non-AIDS death (6). In a recently published study that retrospectively examined the causes of death between 1991 and 1998 in HIV-1 seropositive individuals, end-stage liver disease was found to be the leading cause among hospitalized HIV-seropositive individuals (7). Most of these individuals were HCV-positive.
III. Pathogenesis of HCV
The immune response to HCV is yielding important new information regarding host/viral interactions. A broad and strong anti-HCV specific CD4+ immune response is an important determinant of recovery during the acute phase of HCV (8) and in the prevention of severe HCV recurrence after hepatic transplantation (9). Vigorous HCV-specific CD8 immunity distinguishes individuals with self-limited HCV infection from individuals with chronic HCV infection (10, 11). Both CD4+ and CD8+ responses to HCV structural proteins (core, E1, E2) are important determinants of a successful outcome to therapy. HIV may have a deleterious effect on HCV specific immune responses in coinfected patients, which may be one of the reasons why higher CD4+ T cell counts and lower HCV viremia have been associated with improved responsiveness to interferon (12-16).
IV. Similarities and differences between HIV and HCV
Viral replication: Chronic infection with both HIV-1 and HCV are characterized by dynamic equilibrium between virus production and clearance. As determined by plasma apheresis (see just below), the estimated daily virion production for HIV-1 is 9.3 log10 - 10.2 log10 and for HCV is 11.6 log10 - 13.0 log10 (17). These data suggest that large numbers of virus particles are produced each day.
Plasma apheresis is a procedure that is used to remove plasma without removing the cellular components of the blood. It is a method that has been used to measure virion production for HCV and HIV.
Pathogenesis: The central pathogenic mechanisms, whether direct viral cytotoxicity (direct killing of cell by infected virus) or the host's immune response, have not been conclusively established for either virus, although each mechanism has been hypothesized to be important in each viral infection. The differences in clinical features of the disease result directly from differences in disease pathogenesis. Infection with HIV results in progressive immune dysfunction, secondary to the continued loss of CD4+ T cells, and the eventual onset of opportunistic infections. HCV is a hepatotropic virus, and the eventual consequence of HCV infection is the development of liver failure. The symptoms associated with end stage HIV infection result directly from pathogenic infection (i.e. pulmonary symptoms with pneumocystis carinii pneumonia or odynophagia from esophageal candidiasis). In contrast, end stage liver disease in HCV results from hepatic fibrosis, a response that can occur to a variety of insults including viral hepatitis, autoimmune attack of hepatocytes, alcohol abuse, drugs, or metabolic diseases due to an overload of iron or copper (18). The normal liver contains an epithelial component (hepatocytes), an endothelial lining, tissue macrophages (Kupffer cells and perivascular mesenchymal cells (stellate cells). Stellate cells are the key fibrogenic cell; they become activated, transition from quiescent cells into proliferative, fibrinogenic, and contractile myofibroblasts, in response to hepatic injury of any etiology (19). TGF-b is the major stimulus for stellate cell production of fibrin (18).
Several studies have evaluated the determinants of hepatic fibrosis in HCV monoinfected and HIV/HCV coinfected individuals (20). Poynard et al (1997) found that age greater than 40 years at the time of HCV acquisition, alcohol consumption of 50 g or more and male sex are independently associated with accelerated hepatic fibrosis. Benhamou et al (1999) found that HIV seropositivity and severe immunosuppression (CD4 cell count < 200 cells/mm3, and alcohol consumption were all associated with a higher fibrosis progression rate in HIV/HCV coinfected individuals (21). Puoti et al (2001) recently reported an independent association between CD4+ cell count < 500 cells/mm3 and the presence of fibrous septa (odds ratio, 3.2; P = 0.037) (22). Powell et al (2000) demonstrated an association between individuals who inherit high TGF-b1 and angiotensinogen (AT)-producing genotypes and the development of progressive hepatic fibrosis (23).
V. Management of HCV Infection
A. Assessment of disease severity
In HIV-infected individuals, quantitation of the amount of HIV-1 RNA in plasma is both an important predictor of disease progression and a measurement of the efficacy of antiretroviral therapy. Additionally, the peripheral blood CD4+ T cell count provides important information concerning the severity of the disease. In HCV, several indicators can be used to assess the degree of disease severity: biochemical measurements (serum quantitation of alanine aminotransferase, ALT), virologic measurements (measurement of HCV RNA), and histologic measurements (degree of fibrosis and inflammation on liver biopsy). Unfortunately, symptoms do not usually present in chronic HCV infection until the development of end stage liver disease. These symptoms (ascites, encephalopathy, prolonged prothrombin time, elevated bilirubin, decreased serum albumin) comprise the Childs-Pugh scoring system, the most frequently used measure to assess damage in end stage liver disease.
B. Role of Liver Biopsy in Hepatitis C
The liver biopsy is the most specific test for the diagnosis and assessment of hepatic pathology (24). The first liver biopsy was performed in 1883 (25) and the technique became widely used as a diagnostic method for liver disease in the late-1950s (26). Liver biopsies can be performed through the abdominal wall (percutaneous), through the jugular vein (transjugular), or through a laparoscope (laparoscopic liver biopsy) (27).
The biopsy specimen represents 1/50,000 of the total mass of the liver, which is usually sufficient for the assessment of diffuse hepatic disease (28). In the management of chronic hepatitis C, the assessment of hepatic pathology can provide important information regarding the prognosis and management of the infection (29). In HCV, the amount of hepatic fibrosis, as opposed to the level of HCV RNA, is the most important prognostic factor. Currently, the only method by which to quantitate the amount of hepatic fibrosis is through a liver biopsy, which should be performed in any HCV-infected individual being considered for treatment. The biopsy is graded for the amount of inflammation (30) and the stage of fibrosis (31) on a 0 to 4 scale (see Ref 32 for review). Treatment should be more aggressively pursued in a patient who has stage 2-3+ fibrosis in the liver. Additionally, there is a poor correlation between the aminotransferase level (ALT) and hepatic histological features that may result from HCV. A subgroup of HCV infected individuals may have normal aminotransferase levels with clinically significant fibrosis or cirrhosis (33). Therefore, most hepatologists recommend a liver biopsy for histologic assessment of the liver regardless of the aminotransferase or HCV RNA levels.
Although very rare, intraperitoneal hemorrhage is the most serious complication of a percutaneous liver biopsy usually occurring within the first two to three hours after the procedure (34). We routinely use ultrasound immediately before the biopsy to localize the site and after the biopsy to make sure that there is no evidence of postprocedure hemorrhage. If hemorrhage is suspected, arrangements for blood, platelet, and plasma transfusions are made. We also alert the interventional radiologists and the surgeons that angiography or intraabdominal surgery may be necessary. In most cases, post-procedure hemorrhage can be managed conservatively.
Liver biopsies are usually performed on an outpatient basis provided that: 1) a reliable individual is able to escort the patient home and is able to stay with the patient overnight after the biopsy, 2) the biopsy was performed in a facility with an approved laboratory, a blood-banking unit, and an inpatient unit (35). Patients who have a liver biopsy should be monitored for 4-6 hours after the procedure. Ultrasonography, may also reduce the risk of complications from the liver biopsy by identifying clinically silent mass lesions and can define the hepatic anatomy relative to the gall bladder, lungs and kidneys (24).
In the event of contraindications to a percutaneous liver biopsy (i.e. uncooperative patient, history of unexplained bleeding, tendency to bleed [prothrombin time > 3-5 sec more than control, platelet count <50,000/mm3, prolonged bleeding time (> 10 min), or use of nonsteroidal antiinflammatory drug within previous 7-10 days], suspected hepatic hemangioma or echinococcal cyst), the biopsy can be obtained through the transjugular approach (36). Liver biopsies can also be performed via the laparoscope, although the frequency with which this procedure is performed has decreased in recent years.
VI. Treatment of HCV
How is the effectiveness of treatment for HCV evaluated? The same measurements that are used to determine disease severity (ALT, HCV RNA, and histological appearance on liver biopsy) are also used to determine if a therapeutic response has been achieved. The timing of a therapeutic response is also important, i.e. whether the response occurs at the end of the treatment period (end of treatment response) or six months after treatment is discontinued (sustained virologic response).
How is HCV treated? Initially, interferon monotherapy (three million units three times per week) was used for the treatment of HCV (37). In 1998, two multicenter randomized trials demonstrated that the combination of interferon alfa-2b plus ribavirin was more effective than interferon monotherapy in the treatment of previously untreated (naïve) patients with chronic hepatitis C (38, 39). Recently, interferon has been conjugated to polyethylene glycol, which results in once a week dosing. Schering-Plough Corporation has attached its product, interferon-a 2b, to a 12k Dalton molecule while Roche Laboratories has attached its product, interferon-a 2a, to a 40k Dalton molecule. Additional improvements in the SVR may occur as a result of basing the dose the pegylated interferon and ribavirin on an individual's body weight.
(Editorial note from Jules Levin) In studies of the Schering pegylated interferon (PegIntron) interferon is prospectively dosed based on patient body weight. And clearly the highest dose studied (1.5 ug/kg) has the most success in reducing HCV viral load. In studies of the Roche pegylated interferon (Pegasys) the same dose is used for all as Roche feels their interferon is best suited and is effective when used that way. In the PegIntron/RBV study Schering treated patients with PegIntron 1.5 ug/kg and 800 mg of RBV daily. After the study they went back and said patients with lower weights who received higher concentrations of RBV had higher response rates. As a result they are recommending patients receive RBV doses in therapy based on their weight.
Since the study they conducted was NOT prospective--meaning they did not study patients who received RBV dosing based on their weight from the beginning of therapy to see if better safety and antiviral results occur--this raises a question as to whether RBV should be weight based dosed. European regulatory authorities approved PegIntron/RBV with RBV weight based dosing.
US FDA regulatory officials have not yet decided whether to approve RBV weight based dosing as of this date (August 14 2001). Roche Pegasys studies have not used weight based dosing of RBV but are starting to analyze their data to see if it does improve response rates. Roche suggests that since people with lower weight respond better to therapy we don't know if the improved responses seen in the PegIntron analysis were due to lower weight or higher concentrations of RBV. Also in question is the safety of higher concentrations of RBV particularly in HIV-infected patients who may have a predisposition to anemia.
Unlike HIV, it may be possible to eradicate HCV and the optimal duration of therapy has become an important issue. Five independent characteristics have been associated with a sustained virological response: genotype 2 or 3, baseline viral load less than 3.5 million copies/mL, no or minimal portal fibrosis, female gender, and age less than 40 (40). Recently, Poynard et al (2000) suggested that all HCV-infected individuals be treated for 24 weeks at which time HCV RNA should be determined by PCR. If HCV RNA is detectable, treatment can be stopped. If the PCR is negative and the patient has fewer than four favorable factors, treatment should be continued for an additional 24 weeks.
(Note from Jules Levin:
Previous studies of standard interferon a-2b 3 MIU with ribavirin daily in HCV
monoinfected yielded overall sustained virologic response rates (SVR) of about
40%.Results from recently reported initial studies using pegylated interferon
with ribavirin in monoinfected yielded overall SVR of 54-61%. Factors affecting
response rates include adherence, genotype, viral load, and stage of liver disease.
Studies have not well established response rates for HCV/HIV coinfected, but
it is suspected that overall response rates may be less: genotype 1 is more
prevalent in coinfection; HIV may hamper response to HCV or therapy. Recently
reported data at DDW 2001 and AASLD 2000 from the Benelux Study suggest 18 months
therapy may be more effective in improving response to therapy and relapse rate
in hard-to-treat populations such as genotype 1, high HCV viral load, HCV/HIV
coinfection. Data from a number of studies suggest that interferon's antifibrotic
effect may slow or stop disease progression despite a lack of sustained virologic
response. Therefore, maintenance therapy using prolonged interferon may be important
for individuals with advanced HCV unable to achieve sustained virologic response.
Maintenance therapy can consist of reduced dose interferon for ongoing periods
of time. Prior to pegylated interferon 1 to 1.5 MIUs per day was the often used
dose for maintenance therapy. Using pegylated interferon, half of the recommended
dose may be used for maintenance therapy).
Review of Benelux Study: Highlights from the 36th Annual Meeting of EASL - Part 2
Several studies in HCV monoinfected individuals have suggested that an immune response directed against HCV is an important determinant of the likelihood of a successful response to therapy, and several studies have suggested that a higher CD4+ cell count is associated with improved outcome in the treatment of HCV in HIV/HCV coinfected individuals. Early initiation of anti-HCV therapy, prior to the loss of HCV-specific CD4+ T cells, may improve the efficacy of anti-HCV therapy in HIV/HCV coinfected individuals. Furthermore, delaying HCV therapy may necessitate the treatment of HIV and HCV simultaneously with multiple medications. Therefore, we believe that therapy for hepatitis C virus should be initiated as early in the course of HIV disease as possible. Clearly further investigation is necessary to more accurately define the optimal timing and treatment for HCV in HIV/HCV coinfected individuals.