The HCV and HIV Coinfected Patient: What Have We Learned About Pathophysiology?

Andrew H. Talal, MD, MPH, P. Wilfredo Canchis, MD, and Ira M. Jacobson, MD;
Weill College of Medicine, Cornell university, NYC

Current Gastroenterology Reports 2002, 4:15-22 Current Science Inc. ISSN 1522-8037

Hepatitis C virus (HCV) infection is an important problem in individuals who are also infected with HIV. HCV infection is very common in HIV-infected individuals, occurring in approximately one quarter to one third of this group, presumably as a consequence of shared routes of trans-mission related to virologic and pathogenic aspects of the viral infections. Although both are single-stranded RNA viruses and share similar epidemiologic properties, there are many important differences. Although the quantity of HIV RNA in plasma is an important prognostic determinant of HIV infection, this has not been shown with HCV. A direct relationship is apparent between HIV-related destruction of CD4 cells and the clinical consequences of the disease resulting from immunodeficiency. The patho-genesis of HCV, which occurs as a consequence of hepatic fibrosis, is much more complex. The hepatic stellate cell, the major producer of the extracellular matrix protein, is the main contributor to hepatic fibrosis, but the mechanism by which HCV induces hepatic fibrosis remains unclear. Treatment of HCV is increasingly important in HIV-infected patients due to improved HIV-associated morbidity and mortality and due to the frequency with which HCV occurs in patients with HIV-HCV coinfection. Timing of treatment initiation, management of side effects, and possible effects of anti-HCV therapy on HIV are among the issues that need consideration. Also, because several issues concerning HCV are unique to coinfected patients, further research is needed to determine optimal management of HCV in this setting.

Introduction

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are similar in many respects. Both viruses have a single-stranded RNA genome, both have very high levels of viral replication, both cause chronic infection, and the two viruses share similar routes of transmission. However, HIV and HCV are also different in many respects. Many of the differences in the clinical manifestations, pathogenesis, and treatment of these viruses can be attributed to differences in the target cell of each virus- the hepatocyte for HCV and the CD4 + cell for HIV. >From an epidemiologic standpoint, HCV is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. In the United States, HCV infection is the main indication for liver transplantation. Recently, HIV-associated morbidity and mortality have declined dramatically as a result of potent antiretroviral therapy. Concomitantly, the incidence of liver disease is increasing in HIV-infected individuals, a large proportion of which can be attributed to HCV infection. The epidemiology, disease course, and management of HCV are different in HIV-HCV coinfected individuals compared with HCV-monoinfected individuals. This review focuses on current advances in HCV-HIV coinfection, particularly in the area of HCV pathogenesis in coinfected patients. In addition, we discuss the epidemiology, diagnosis, and treatment of HCV in coinfected individuals.

Epidemiology

Approximately 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 [1]. Approximately 200 million individuals worldwide have been exposed to HCV [2]. The factors most frequently implicated in HCV trans-mission are blood transfusion before 1990 and intra-venous drug use, although in some cases no risk factors can be found [1,3]. In comparison, about 30% of the 800,000 HIV-infected individuals in the United States are coinfected with HCV as a consequence of shared transmis-sion routes [4oo]. HIV-HCV coinfected individuals have increased risk of sexual and maternal-fetal transmission of HCV virus [5,6]. Maternal-fetal transmission is not common, having a reported prevalence of 1.7% among HCV-monoinfected individuals; the rate of transmission is increased to 19.4% among women coinfected with HIV [7]. Recent studies suggest that, in the era of potent anti-retroviral therapy, the number of deaths caused by liver disease in HIV-1-infected individuals has been increasing. In a cohort of approximately 4000 individuals, liver disease was the primary cause of non-AIDS death [8]. In a recently published study that retrospectively examined the causes of death between 1991 and 1998 in HIV-1-seroposi-tive individuals, end-stage liver disease was found to be the leading cause among those who were hospitalized [9]. The majority of these individuals were HCV positive.

Pathogenesis of HCV

Hepatitis C virus, a member of the Flaviviridae family [10] based on its genome sequence, has been classified into at least six genotypes and more than 50 subtypes. Genotype 1 is the most common in the United States, Europe, and Japan followed by genotypes 2 and 3. Genotype 4 is found in the Middle East and in Central Africa. Genotype 5 is confined to South Africa. Genotype 6 is distributed throughout Southeast Asia [11]. The mechanisms responsi-ble for tissue injury in HCV infection are not well under-stood. HCV cell targets are hepatocytes and possibly B lymphocytes [12].

Mortality due to HCV results from progressive hepatic fibrosis that can lead to cirrhosis and its complications. The clinical manifestations of HIV infection are usually systemic, whereas those of HCV relate principally to the liver. Because of the loss of CD4 + cell function, the primary consequences of HIV infection result from immuno-deficiency. As a result of HCV target cell localization in the liver, the infection is principally concentrated in that organ. Its clinical manifestations, usually first evident during late-stage disease, primarily result from the accu-mulation of hepatic fibrosis and ultimately may culminate in hepatic dysfunction.

Significance of HIV and HCV RNA determinations

Chronic infection with both HIV and HCV is character-ized by dynamic equilibrium between virus production and clearance. Studies of viral kinetics, in which mathe-matical modeling is applied to the viral decay in response to antiviral medications or after procedures such as plasma apheresis that perturb the steady state, have been helpful in clarifying the viral life cycle. Both HIV and HCV have very rapid life cycles, with an estimated daily virion production of 9.3 log 10 to 10.2 log 10 for HIV and 11.6 log 10 to 13.0 log 10 for HCV, indicating that viral turnover is even faster in HCV than it is in HIV infection [13]. The viral set point, the quantity of HIV RNA in plasma 6 months after seroconversion, is an important prognostic parameter in HIV infection. The set point indicates how likely an individual is to progress to AIDS during the next 5 years [14]. During primary HIV infection the HIV RNA level increases rapidly as virion production greatly out-paces virion clearance. During the first 6 months after seroconversion, the immune system is able to gain partial control over viral replication, and the level of HIV RNA in plasma is decreased. During the asymptomatic phase of the infection, a steady state is achieved in which virion production equals virion clearance, presumably by the immune system. However, a progressive destruction of CD4 + cells eventually results in profound immuno-deficiency. Without effective treatment, most individuals become symptomatic during late-stage disease as a conse-quence of various opportunistic infections. The symptoms present during late-stage disease usually result from immunodeficiency, which allows opportunistic infections to be established.

The relationship between the quantity of HCV RNA in serum, the pathogenesis of the disease, and the develop-ment of clinical symptoms is not as straightforward in HCV infection. The hepatic stellate cell (HSC) is the main fibrogenic cell type in the liver, and it is the principal culprit in the pathogenesis of HCV [15]. Many different stimuli can lead to HSC activation, most notably inflam-mation in the liver. The hepatic inflammatory infiltrate within the liver can lead to secretion of transforming growth factor-o (TGF-o ), which can lead to HSC activation and secretion of extracellular matrix (ECM) protein [16]. Although a direct correlation between the quantity of HCV RNA in serum and HCV pathogenesis has not been made, the quantity of HCV RNA is one of the five determi-nants of an increased likelihood of a successful outcome to antiviral therapy [17].

Significance of immune response against each virus

We have learned much about the importance of the immune response against HIV. Although the hope of viral eradication was harbored by many researchers and practi-tioners shortly after the development of the HIV protease inhibitors, time has demonstrated that our efforts at HIV eradication have been thwarted thus far. However, it does appear that early initiation of antiretroviral therapy, prior to seroconversion, may alter the course of HIV as a result of the retention of potent HIV-specific cellular immune responses that may delay disease progression. Novel approaches to the treatment of HIV involve boosting the immune response through a variety of mechanisms to achieve immune-mediated virus suppression in the absence of therapy. This approach has been demonstrated through "structured treatment interruptions" that have recently become popular.

The immune response plays an important role in HCV pathogenesis [18]. A broad and strong anti-HCV-specific CD4 + immune response is an important determinant of recovery during the acute phase of HCV [19,20] and in the prevention of severe HCV recurrence after hepatic transplantation [21]. Vigorous HCV-specific CD8 immu-nity further distinguishes individuals with self-limited HCV infection from individuals with chronic HCV infec-tion [22,23]. Even in patients with chronic HCV infection, a strong HCV-specific CD4 response may help protect these individuals against progressive liver disease [20]. Moreover, both CD4 + and CD8 + responses to HCV structural proteins (core, E1, and E2) are important deter-minants of a successful outcome to therapy. Through the destruction of CD4 + cells with reactivity for HCV, HIV may have a deleterious effect on 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 (IFN) [24-26]. Because IFN may also result in a dose-dependent decrease in CD4 + T cells, it is impor-tant to initiate treatment as early in the course of HIV infection as possible prior to the onset of severe immuno-deficiency [27,28].

The central pathogenic mechanisms, whether direct viral cytotoxicity or the immune response of the host, have not been conclusively established for either virus, although each mechanism has been hypothesized to be important in each viral infection. Recent reports have demonstrated that the rate of hepatic fibrosis is accelerated in HIV-HCV coinfected individuals [29oo,30o,31,32o]. Several studies have evaluated the determinants of hepatic fibrosis in HCV-monoinfected and HIV-HCV coinfected individuals. In HCV infection, age over 50 years, consumption of 50 g or more of alcohol per day, and male gender are indepen-dently associated with accelerated hepatic fibrosis [33,34]. In HIV-HCV coinfected individuals, HIV infection, alcohol consumption of more than 50 g/d, CD4 cell count less than 200 cells/µL, and age over 25 years at the time of HCV acquisition are all associated with accelerated hepatic fibrosis [29]. Puoti et al. [32] found an independent associ-ation between CD4 + cell count less than 500 cells/mm 3 and increased rate of fibrous septa formation. A recent study found that chronic use of antiretroviral therapy containing at least one protease inhibitor, younger age at the time of HCV infection, low alcohol intake, and high CD4 count were associated with a reduced hepatic fibrosis progression rate in HCV-HCV coinfected individuals [35].

The pathogenic mechanisms by which increased hepatic fibrosis in HIV-HCV coinfected individuals occurs have yet to be determined conclusively. However, immuno-logic differences in HIV-HCV coinfected and HCV-monoinfected individuals may account for the different rate of hepatic fibrosis, because the inflammatory response has been shown to be an important determinant of fibrosis in humans [34]. In preliminary evaluation we showed that the number of proliferative and apoptotic liver cells were increased in HCV-monoinfected and HCV-HIV coinfected individuals, compared with uninfected individuals [36]. Upon further study, we found that CD4 + cells are signifi-cantly decreased and that periportal hepatocyte prolifera-tion is increased in HIV-HCV coinfected individuals, compared with HCV-monoinfected individuals [37]. Deficient cytolytic activity and ineffective CD4 priming of CD8 responses may lead to dysfunctional CD8 + cells in HIV infection that are deficient in cytolytic activity, impairing their ability to clear infected hepatocytes, but retaining their ability to secrete cytokines [38,39]. These cytokines may lead to hepatocyte injury, resulting in phagocytosis by Kupffer cells, activation of hepatic stellate cells, and deposition of hepatic fibrosis (Fig. 1). Our findings suggest that the resulting hepatocyte injury may also stimulate de novo hepatocyte proliferation. In HCV, dysfunctional peripheral blood CD8 + T cells are also characterized by impaired cytolytic activity. In contrast to the situation in HIV, antiviral cytokine secretion is diminished in these cells [40]. However, the existence of dysfunctional intra-hepatic CD8 + cells in HCV remains to be evaluated. Finally, a dependence of fibrosis on T-helper 2 responses, which are disproportionately preserved in HIV patients, has been documented in IFN-o -deficient knockout mice [41] and in schistosomiasis [42].

Clinical Manifestations

Most HIV- and HCV-infected individuals do not develop symptoms until late in the course of their disease. During the initial stages of HIV infection, patients usually present with symptoms similar to those in infectious mononucleosis, including fever, lymphadenopathy, myalgias, arthal-gias, and sweating [43]. The clinical consequences of the infection result directly from immunodeficiency. The symptoms in acute HCV infection are typically those seen with other forms of hepatitis: jaundice, scleral icterus, fatigue, and weakness. However, the occurrence of acute symptoms may indicate important differences in disease pathogenesis. For example, whereas the acute seroconver-sion syndrome occurs in the majority of HIV-infected individuals, some have suggested that the presence of symptoms during the acute phase of HCV infection is associated with an increased likelihood of viral clearance [44]. The symptoms that usually occur in late-stage HCV infection (ascites, encephalopathy, prolonged prothrom-bin time, elevated bilirubin, and decreased serum albumin) comprise the Child-Pugh scoring system, the most frequently used measure to assess damage in end-stage liver disease.

HCV diagnosis in HIV-HCV coinfected individuals

With the realization that HCV is a frequent pathogen in HIV-infected individuals, the United States Public Health Service and the Infectious Disease Society of America issued guidelines in 1999 stating that all HIV-infected individuals must be screened for anti-HCV antibodies [45]. With respect to these recommendations, the concern has been raised regarding the most appropriate screening test, whether measurement of anti-HCV antibodies, as determined by enzyme-linked immunosorbent assay (ELISA), or HCV RNA, as determined by polymerase chain reaction (PCR). Initially the concern was expressed that HIV-associated immunodeficiency might result in false negative ELISA results. However, recent investigations have shown that the predictive value of the anti-HCV ELISA is significantly better in HIV-HCV coinfected individuals than it is in HCV-monoinfected individuals [46]. The third-generation ELISA should be performed to screen for HCV in HIV-HCV coinfected individuals [47].

Management of HCV Infection in HIV-HCV Coinfected Individuals 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 and the likelihood of a successful therapeutic outcome [48]. In HCV, the amount of hepatic fibrosis, as opposed to the level of HCV RNA, is the most important prognostic factor. However, quantita-tion of serum HCV RNA and determination of the HCV genotype are important predictors of the likelihood of therapeutic efficacy. Liver biopsy is the most specific test for diagnosis and the assessment of hepatic pathology [49], and currently, it is the only method by which to quantify the amount of hepatic fibrosis. The biopsy is graded on the amount of inflammation and on the stage of fibrosis on a 0-to-4 scale [50-52]. Most hepatologists recommend a liver biopsy for histo-logic assessment of the liver, regardless of aminotransferase or HCV RNA levels, because there is a poor correlation between the aminotransferase level and the hepatic histo-logic features that may result from HCV. For example, a subgroup of HCV-infected individuals have normal aminotransferase levels despite clinically significant fibrosis or cirrhosis [53]. To arrest disease progression, we believe that treatment should be more aggressively pursued in patients with stage 2 or stage 3 fibrosis in the liver. Therapeutic options At least 15 antiretroviral medications directed against specific portions of HIV have been approved by the US Food and Drug Administration (FDA). In contrast, agents used to treat HCV-IFN, IFN modified with polyethylene glycol (PEG), and RBV-are nonspecific viral agents. The precise mechanisms of action of IFN and RBV have not been discerned, but they appear to involve both antiviral and immunomodulatory effects, and both effects appear to be important in achieving therapeutic success. In HCV, several indicators can be used to assess the degree of disease severity and therapeutic efficacy. These include biochemical measurements (serum quantitation of alanine aminotrans-ferase), virologic measurements (HCV RNA), and histologic measurements (degree of fibrosis and inflammation on liver biopsy). Because clinical symptoms do not usually present in chronic HCV infection until the development of end-stage liver disease, symptomatic improvement cannot be used as a means to assess therapeutic efficacy. The timing of a therapeutic response is also important, ie, whether the response occurs at the end of the treatment period (ETR) or 6 months after treatment is discontinued, with the latter instance referred to as sustained virologic response (SVR). Because HCV does not have a nuclear phase during its replication cycle and does not integrate into the host genome as HIV does, HCV eradication may be a realistic therapeutic target. Long-term follow-up studies have suggested that individuals who achieve an SVR are very unlikely to have HCV recurrence [54,55]. Combination therapy with IFN and RBV has been the standard treatment for HCV [56]. IFN can decrease the level of HIV, and it may prolong survival in HIV-mono-infected individuals [57]. However, IFN attenuates the CD4 + cell response to HIV when it is combined with nucleoside analogues [58]. Investigators in a French prospective study reported that the response to IFN in chronic HCV infection was not statistically different in HCV-monoinfected individuals, compared with HIV-HCV coinfected individuals [59].

The efficacy of IFN and RBV in HIV-HCV coinfected individuals has been documented in four published studies, including a total of 109 individuals (Table 1) [60,61o,62,63]. All of these studies were conducted in Europe. Three of the studies included primarily HCV-therapy na•ve individuals. In three of the studies, intra-venous drug use was the primary risk factor for HCV disease. The vast majority of study participants had between 300 and 500 CD4 lymphocytes/mm 3 and were on antiretroviral therapy. All study participants received combination therapy with IFN and RBV for 6 to 12 months and achieved an SVR of 11% to 40%.

Recently IFN has been conjugated to polyethylene glycol (PEG), allowing weekly dosing and bringing more sustained IFN levels [64]. Additional improvements in the sustained virologic response may occur as a result of basing the IFN and RBV doses on the body weight of the individual [65]. Studies of the efficacy of PEGylated IFN (PEG-IFN) and RBV in HIV-HCV coinfection are currently in progress.

Side effects of treatment

Because of the relatively increased frequency of side effects with PEG-IFN and RBV, the ability to tolerate these medica-tions is another issue that warrants careful consideration in HIV-HCV coinfection. RBV is a guanoside nucleoside analogue with antiviral activity against a variety of RNA and DNA viruses, not including HIV [61]. In vitro RBV can phos-phorylate the HIV reverse transcriptase inhibitors, particu-larly zidovudine and stavudine (D4T), which could result in vivo in increased plasma HIV RNA [62,63]. However, in studies to date, significantly increased HIV RNA levels have not been a major problem in RBV-treated individuals who were also treated with HIV reverse transcriptase inhibitors. Anemia and neutropenia, both of which are common side effects in HCV-infected patients who are prescribed IFN and RBV, may be particularly problematic in HIV-HCV coinfected patients. RBV can cause hemolytic anemia, and IFN can cause bone marrow suppression resulting primarily in neutropenia but also in anemia. Anemia, which is more prevalent in HIV-infected individuals compared with the general population, is usually multi-factorial in HIV infection. Multiple antiretroviral medica-tions, including nucleoside analogues that are associated with bone marrow suppression and HIV infection itself, can contribute to anemia in these individuals. The use of growth factors, granulocyte colony stimulating factor or erythropoietin, may be beneficial in treating these side effects, particularly in HIV-HCV coinfected patients.

Duration of therapy

In the treatment of HCV, the optimal duration of therapy has become an important issue. Five independent charac-teristics have been associated with a sustained virologic 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 years [17]. Recently, Poynard et al. [64] 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 PCR is negative and the patient has fewer than four favorable factors, treatment should be continued for an additional 24 weeks. Whether the same factors also predict an increased likelihood of a successful therapeutic response is yet to be determined, as is the optimal duration of HCV treatment in HIV infection.

Conclusions

Several studies in HCV-monoinfected individuals have suggested that an immune response directed against HCV is important to achieve a successful response to therapy. It has also been 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 decrease of CD4 + T cells, may improve the efficacy of anti-HCV therapy in HIV- HCV coinfection. Furthermore, delaying HCV therapy may necessitate treatment of HIV and HCV simulta-neously with multiple medications, some of which may have hepatotoxic effects. Therefore, we believe that therapy for HCV should be initiated as early as possible in the course of HIV disease. Additionally, initiation of anti-HCV therapy early in the course of HIV may decrease if not halt the progression to cirrhosis. In individuals with severe immunodeficiency, initiation of antiretroviral therapy before anti-HCV therapy should be considered to improve patients' immune status and decrease HIV replication. Clearly, further investigation is necessary for a more accurate definition of the timing of treatment of HCV in HIV-HCV coinfected individuals. In addition, further studies are needed to evaluate the possible mecha-nisms by which antiretroviral therapy may prevent hepatic fibrosis. Given the clinical and epidemiologic importance of HCV in HIV-infected individuals, addi-tional research is necessary to more fully discern the ways in which HCV pathogenesis and immune responses are altered in the setting of HIV.

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