Therapy for coinfection of hepatitis C

Therapy for co infections of hepatitis C : 

Therapy for co infections of hepatitis C Prof. Mohammed Emam Prof. gastro .and hepatology Zagazig university -Egypt 2010

Coinfection with Hepatitis C Virus and HIV: More than Double Trouble : 

Coinfection with Hepatitis C Virus and HIV: More than Double Trouble

Agenda : 

Agenda 1-What is the significance of therapy of coinfection of HCV? 2-What are the common coinfection in HCV patients? 3-What the changes in clinical outcome in those patients? 4-What the ideal therapy for such patients?

Disease progression in chronic hepatitis C: modifiable factors. : 

Disease progression in chronic hepatitis C: modifiable factors. Histological activity and ALT level. . excessive alcohol consumption; smoking (tobacco and marijuana); insulin resistance; and steatosis. and coinfection with hepatitis B virus, human immunodeficiency virus type 1, or schistosomiasis. Iron metabolism. Obesity.

Therapy for co infection of hepatitis B and C : 

Therapy for co infection of hepatitis B and C

What is HBV/HCV Co-infection? : 

What is HBV/HCV Co-infection? . Because the two viruses share similar modes of transmission, co-infection with the two viruses is not uncommon.

Introduction : 

Introduction Available evidence indicates that fibrosis progression and the development of cirrhosis are more frequent and accelerated in HBV–HCV co infection as compared with mono infection by either virus. Moreover, a significantly higher incidence of hepatocellular carcinoma and an excess liver-related mortality were noted in co infection as compared with HBV or HCV infection alone

Incidence : 

Incidence 10% of anti-HCV positive patients may be HBsAg positive. 20% HBV positive patients are co infected with HCV. The possibility that occult HBV ,not detected by HBsAg testing alone, may substantially increase the true prevalence of HBV/HCV dual infection.

Incidence : 

Incidence Three quarters of those patients with HCV who lost HCV RNA with treatment but still had elevated ALT post treatment, may be HBV DNA positive Stuart C. G gastrojournal feb, 2009.

The Egyptian Situation : 

The Egyptian Situation In Egypt, dual infection with HBV and HCV was detected in only 10% which may be attributed to less common drug users while isolated anti-HBc – a marker of previous exposure to HBV – was reported in 45% of chronic hepatitis C patients. This high figure of anti-HBc reflects a common route of transmission of both viruses.. El-Zayadi- Hepatitis B Virus Infection arab j g(2007)

coinfection" or"superinfection : 

coinfection" or"superinfection most HBV-/HCV-positive patients are all "coinfected," however, "superinfection“ were reported, especially among Asians who acquired HBV perinatally, and were infected with HCV later in life.   the shared risk of injection drug use may in fact lead to near-simultaneous coacquisition of both viruses. Such is not the case for the majority of cases globally,

coinfection" or"superinfection : 

coinfection" or"superinfection the long-term prognosis after acute HCV superinfection was worse than HDV superinfection, including higher rates of cirrhosis than among HBV monoinfected patients. Additionally, rates of subsequent hepatocellular carcinoma were higher, that highlight the synergistic role of coinfection on the risk of hepatocellular carcinoma formation.

A confusing mix ? : 

A confusing mix ? Clinical literature provides a confusing mix regarding the effects of HBV on HCV and vice versa, with most reports showing that HCV suppresses HBV, but also that HBV can suppress HCV replication In most cases, HCV predominates over HBV

Slide 15: 

A confusing mix ?

co infection of hepatitis B and C Viral replication : 

co infection of hepatitis B and C Viral replication Reciprocal Viral Interference :  Some authors find an inhibition of hepatitis B by Hepatitis C . others describe shared inhibition which may change over time .

co infection of hepatitis B and C Viral replication: : 

co infection of hepatitis B and C Viral replication: In vitro, the hepatitis C core protein inhibits the hepatitis B enhancer 1 and 2 . (This enhancer sequence has also been shown to Increase the activity of HBcAg gene promoter) This effect was abrogated by removal of nucleotides 1115 to 1236 of the HBV enhancer .

co infection of hepatitis B and C Viral replication : 

co infection of hepatitis B and C Viral replication This effect was mediated through direct interaction between the HBx protein and HCV core protein constructs .(HBx protein is a small transcriptional activator that is essential for virus infection. HBx is thought to be involved in viral hepatocarcinogenesis because it promotes tumorigenesis

co infection of hepatitis B and C Viral replication: : 

co infection of hepatitis B and C Viral replication: In addition, HCV core protein was able to complex with HBV polymerase, which prevented HBV virion formation. Therefore, virus-virus interaction can occur at multiple levels and further differential modulation of the immune system may be superimposed on these processes.

co infection of hepatitis B and C Viral replication: : 

co infection of hepatitis B and C Viral replication: In vitro, there is no evidence of direct interference between the two viruses; therefore Brass and Moradpour postulate that the phenomena are due to differences in innate and/or adaptive immune response .

co infection of hepatitis B and C Viral replication : 

co infection of hepatitis B and C Viral replication In recent studies, anti-HCV positive patients were found more often to be HCV-RNA negative in the presence of HBV-DNA suggesting suppression of HCV by HBV

Viral replication : 

Viral replication Occasionally, a super-infection with hepatitis C may even induce clearance of hepatitis B This could be due to the dominant role of HCV in eliciting an immune response Hepatitis D inhibits C viral replication

co infection of hepatitis B and C Viral replication : 

co infection of hepatitis B and C Viral replication Usually, in the evaluation of these patients, 1 of the 2 viruses will predominate; this can generally be determined by the level of serum hepatitis B virus (HBV) DNA or serum hepatitis C virus (HCV) RNA.

a dynamic rather than a static process? : 

a dynamic rather than a static process? In reality, the HBV-/HCV-coinfected patient represents a dynamic rather than a static process, and the "picture in time" awareness of such patients, particularly those in antiviral treatment regimens, may be misleading.

a dynamic rather than a static process : 

a dynamic rather than a static process Unlike the chronic HCV monoinfected patient, wherein viral levels generally remain static and within one-log variation over time, the chronic hepatitis B patient (espcially HBeAg-negative )typically exhibits wide viral variation.

a dynamic rather than a static process : 

a dynamic rather than a static process However, when the two viruses cohabitate the liver, not only do HBV serum levels still fluctuate profoundly, but now HCV likewise exhibits wide and uncharacteristic fluctuations. These large and unpredictable variations in both HCV and HBV viral loads in an individual patient are seemingly sporadic, as the reactivation phase of one virus was independent of "any peculiar modification of the viremia levels of the other.

The virological and molecular aspects of HBV–HCV : 

The virological and molecular aspects of HBV–HCV The virological and molecular aspects of HBV–HCV co infection are poorly understood. Although liver disease activity and progression are generally more severe in the presence of double infection, an inverse relationship in the replicative levels of the two viruses has been noted, suggesting direct or indirect (i.e., mediated through host immune responses) viral interference.

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response Both hepatitis B and hepatitis C are hepatotropic viruses; however, differences exist between these viruses regarding the pattern of injury after acute infection, immune response and the underlying mechanisms that may precipitate injury.

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response Acute HBV acquisition results in a prolonged period of relatively silent infection,. Liver injury seems to be primarily the result of an immune response to infected hepatocytes. The mechanism of HCV-associated injury is less clear. A cytopathic effect has been noted in tissue culture systems, but there is far less evidence for this in vivo

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response The immune response to HBV is strong, and can be associated with control through both humoral pathways (HBsAg:HBsAb binding) and through strong cytotoxic T-cell responses. In contrast, humoral antibody response to HCV is more commonly associated with mutational display, but fail to clear the virus.The cytotoxic T lymphocyte response is relatively poor until the virus is actually cleared, when a strong polyclonal response is frequently observed.

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response There is strong evidence that HCV can modify the infected hepatocyte's natural immune response to infection through mediation of the JAK-STAT and other pathways. The JAK-STAT signaling pathway takes part in the regulation of cellular responses to cytokines and growth factors. Employing Janus kinases(JAKs)or and Signal Transducers and Activators of Transcription (STATs),

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response In contrast, HBV may avoid development of an natural response- not primarily by active interference with interferon-stimulated gene response pathways, but by maintaining key elements of its transcriptional template within the isolated nuclear compartment of the cell.

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response There is adifferential response to FAS-L a type-II( transmembrane protein that belongs to the tumor necrosis factor (TNF) family. Its binding with its receptor induces apoptosis) in HCV- versus HBV-related disease.

HBV and HCV: Pathogenesis and Immune Response : 

HBV and HCV: Pathogenesis and Immune Response Tumor necrosis factor-β, interleukin (IL)-1β, IL-6, IL-8, and transforming growth factor-β levels are all higher in HBV-HCV-coinfected individuals than with separate infections.

Clinical outcome: : 

Clinical outcome: The data are quite controversial: coinfection to increase chronicity and cirrhogenesis another study, dual infection reduced histologic severity but not chronicity Co-infection with hepatitis B appears not to be a risk factor for the development of cirrhosis in patients with hepatitis C while alcohol consumption is.

Clinical outcome: : 

Clinical outcome: Dual infection conveyes increased risk for development of hepatocellular carcinoma Co-infected livers exhibit no particular differences and the pattern of lesions does not allow differentiation between the role a given virus is playing A special role is occupied by the gathering 'anti-HBc alone': such patients have lower RNA levels but a higher prevalence of cirrhosis also

Clinical outcome : 

Clinical outcome In transplanted patients, hepatitis C appears to ameliorate the course of hepatitis B; in particular there was no graft loss due to fibrosing cholestatic hepatitis .

Treatment: : 

Treatment: Few data exist on treatment of double infection. The approach to therapy for patients coinfected with hepatitis B and hepatitis C involves treating the predominant infection.

If hepatitis C is predominant : 

If hepatitis C is predominant Treatment should be initiated with a combination of pegylated interferon and ribavirin. Pegylated interferon may have a suppressive effect on HBV, as pegylated interferon is approved for the treatment of hepatitis B infection, The goal of therapy in hepatitis C-predominant disease is to eradicate HCV and have a sustained viral response.

Treatment: : 

Treatment: Patients treated with PEG-IFN + ribavirin have similar SVR with respect to monoinfected but in responders there is a high degree of HBV-DNA reactivation . Yu JW, Sun LJ, Zhao YH et al. (2009) Brass V & Moradpour D (2009). New insights into hepatitis B and C virus coinfection. J Hepatol 51: 423-425

Treatment: : 

Treatment: Silent co-infection with HBV decreases the response to interferon in patients treated for hepatitis C ; the same holds true for 'anti-HBc alone' . by down-regulation of type-I interferon receptor gene expression in the liver. J. Med. Virol.(2008) 63: 220-227.

If hepatitis B is the predominant virus : 

If hepatitis B is the predominant virus Treatment should be initiated for HBV infection. Currently approved therapies for hepatitis B infection include interferon, pegylated interferon, lamivudine, adefovir, entecavir, and telbivudine. .

If hepatitis B is the predominant virus : 

If hepatitis B is the predominant virus Care should be taken when initiating these regimens because interferons should not be used in patients with hepatitis B-related cirrhosis and lamivudine should not be used at all secondary to concerns regarding the development of antiviral mutations

If hepatitis B is the predominant virus : 

If hepatitis B is the predominant virus Once treatment is initiated, the goal of therapy is similar to that for the monoinfected hepatitis B patient: The goal of therapy in patients infected with wild-type virus is e antigen seroconversion, whereas the goal of therapy in patients infected with precore mutant strains is prolonged viral suppression

Slide 46: 

Results of interferon trials for the treatment of HBV/HCV coinfection are mixed, owing in part to evolving regimens and durations, and more sensitive and reproducible HBV DNA assays..

Slide 47: 

More important, many of these studies demonstrate that successful clearance of one virus may lead to reactivation of the other, or "reciprocal viral interference," with HBV flares most frequently described

Slide 48: 

Despite the fact that one third of those dually infected patients with nondetectable HBV DNA levels pretreatment developed HBV reactivation posttreatment, HBsAg clearance occurred in 11.2% of dual-infected patients, many with seroconversion to anti-HBs

Summary and unanswered questions : 

Summary and unanswered questions Should we be checking HBV DNA levels on our HCV monoinfected patients? . It has been suggested that occult HBV disease may decrease response to HCV antiviral therapy irrespective of genotype.

Summary : 

Summary Should oral nucleoside/nucleotide analogs be added pre-emptively to obviate HBV reactivation? Finally, as we enter a new HCV antiviral era that may include triple therapy regimens (interferon, ribavirin, and HCV protease or polymerase inhibitors), how will these new agents interact with HBV in the coinfected population?

Slide 51: 

Now,Less confusing ?

HCV/Schistosomiasis co infection in EGYPT : 

HCV/Schistosomiasis co infection in EGYPT Clinical studies showed 70% to 90% of Egyptian patients with chronic hepatitis, cirrhosis, or hepatocellular carcinoma had HCV infections. Co-infections with schistosomiasis caused more severe liver disease than infection with HCV alone. .

HCV/Schistosomiasis coinfection : 

HCV/Schistosomiasis coinfection Few data are available about the immune response of patients co-infected with hepatitis C and schistosomiasis Schistosomiasis was reported to cause an imbalance in HCV-specific T-cell responses leading to increased viral load, a higher probability of HCV chronicity, and more rapid progression of complications in co-infected persons.

HCV/Schistosomiasis coinfection : 

HCV/Schistosomiasis coinfection Impact of Schistosoma mansoni co-infection on serum profile of interferon-gamma, interleukin-4 and interleukin-10 in patients with chronic hepatitis C virus infection. Emam EA, Emam M, Shehata AE, Emara M. Department tropical and Internal Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt. U.S. National Library of Medicine J Immunol. 2006;13(2):33-40.

HCV/Schistosomiasis coinfection immune response : 

HCV/Schistosomiasis coinfection immune response cytokines may play a crucial role in the host response to hepatitis C virus infection. While T-helper type 1 (Th1) cytokines are required for host antiviral immune responses, T-helper type 2 (Th2) cytokines can inhibit the development of these effector mechanisms.

HCV/Schistosomiasis co infection immune response : 

HCV/Schistosomiasis co infection immune response Patients co-infected with HCV and S. mansoni had necro-inflammatory scores significantly higher in comparison to patients infected with HCV alone Th1/Th2 cytokines imbalance is probably involved in the pathogenesis of chronic HCV infection. S. mansoni co-infection induces more alteration in the cytokine background along with more-severe liver disease.

HCV/Schistosomiasis coinfection immune response : 

HCV/Schistosomiasis coinfection immune response . At baseline, subjects with HCVinfection alone had stronger multispecific intrahepatic HCV-specific T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver.

HCV/Schistosomiasis coinfection : 

HCV/Schistosomiasis coinfection Schistosomiasis may downregulate the stimulatory effect of hepatitis C virus on Th1 cytokines and this may lead to chronicity of hepatitis C infection in co-infected patients (El Kady et al. 2004). However, serum levels of TNF-a ,TGF b, a Th1 cytokine, were significantly higher in the co-infected group than hepatitis C group.

HCV/Schistosomiasis coinfection immune response : 

HCV/Schistosomiasis coinfection immune response . IL-13 is considered to be the major fibrogenic mediator in murine schistosomiasis and recent studies in humans associated high levels of this cytokine with the development of more severe hepatic fibrosis (Ribeiro-de-Jesus et al. 2004),

cryoglobulinaemia : 

cryoglobulinaemia Chronic helminthic infections have been found to decrease the incidence and manifestations of immune-related diseases. There is an apparent protective effect of S. mansoni coinfection against mixed cryoglobulinaemia in chronic hepatitis C patients.  Liver International, Volume 29, Number 7, August 2009 , pp. 1065-1070(6)

Helicobacter pylori and Hepatitis C virus coinfection : 

Helicobacter pylori and Hepatitis C virus coinfection The association between H. pylori infection and liver cirrhosis in patients with hepatitis C virus has been documented in different parts of the world; nevertheless,

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C the H. pylori positivity was increased significantly in the HCV-infected patients when compared to that in healthy controls,

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C a remarkable increase in H. pylori prevalence with advancing hepatic lesions, and the eradication treatment may prove beneficial in those patients with chronic hepatitis C.

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C In HCV-infected patients, the prevalence of H. pylori infection was increased significantly from chronic active hepatitis to cirrhosis. patients with chronic active hepatitis, Child-Pugh score A, Child-Pugh score B and Child-Pugh score C, respectively. with increasing Meld (model for end-stage liver disease) score. The prevalence of H. pylori was documented in 32.1% patients with Meld score ≤10 and in 41/62 (66.1%) patients with Meld score >10.

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C H. pylori has been reported to induce hepatotoxicity in vitro.   A soluble factor that exhibits cytotoxic effects on a mouse liver cell line was identified in the culture medium of H. pylori and other Helicobacter species.

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C Although H. pylori is generally believed to be sensitive to bile,  several studies have shown that H. pylori is detectable in the liver and biliary tract  and that H. pylori can survive in bile-rich environment.  These findings indicate that bile-resistant H. pylori may survive in the liver and biliary tract

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C The discovery of the presence of helicobacter species DNA in liver material from patients with liver disease has led to the challenging hypothesis that these bacteria may play a role in the evolution of hepatic lesions, from chronic viral hepatitis to cirrhosis and hepatocellular carcinoma (HCC).

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C Helicobacters,, are strong inducers of the inflammatory cascade;  infection with them could lead to the accumulation of extraordinary number of lymphocytes and polymorphonuclear cells in the infected tissue.

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C It has been shown that several Helicobacter spp. could also secrete a liver-specific toxin that causes hepatocyte necrosis in cell culture and might therefore be involved in damaging liver parenchyma in vivo . (Meyer-ter-Vehn et al.

Helicobacter pylori and Hepatitis C : 

Helicobacter pylori and Hepatitis C Despite the availability of these data worldwide, no conclusive data is available about Egyptian patients despite the high prevalence of HCV in Egypt where the predominant genotype is type 4. El-Masry S, El-Shahat M, Badra G, Aboel-Nour MF, Lotfy M. Helicobacter pylori and Hepatitis C virus coinfection in Egyptian patients. J Global Infect Dis 2010;2:4-9

Co infection with hepatitis A and B in HCV patient: : 

Co infection with hepatitis A and B in HCV patient: Fulminant courses of acute hepatitis A or B in patients with chronic hepatitis C have been described Therefore, vaccination is recommended

Co infection with hepatitis D,B and C: : 

Co infection with hepatitis D,B and C: Fulminant courses of acute hepatitis D and B in patients with chronic hepatitis C have been described Therefore, vaccination is recommended

Co infection With Hepatitis B and Hepatitis C Viruses in HIV- Patients : 

Co infection With Hepatitis B and Hepatitis C Viruses in HIV- Patients Over the past few years, HBV and HCV have emerged as significant causes of morbidity and mortality in HIV-infected patients in developed countries, where classic opportunistic infections have declined as a result of the widespread use of potent antiretroviral therapies. Although increasing attention has been paid to HIV/HBV and HIV/HCV coinfections, there are few data on HIV/HBV/HCV triple infection

HBV/HCV and HIV : 

HBV/HCV and HIV Dual chronic infection by HBV and HCV in HIV-positive patients is associated with a high risk of accelerated progression to cirrhosis and hepatocellular carcinoma. Furthermore, it has important implications for hepatitis treatment, choice of antiretroviral regimen, and antiretroviral-associated hepatotoxicity.

HBV/HCV and HIV : 

HBV/HCV and HIV Several studies in HIV-uninfected patients have shown an interplay between HBV and HCV in cases of double infection, with a subsequent inhibition of the replication of 1 or both viruses and a prevalent negative influence of HCV on HBV activity.

HBV/HCV and HIV : 

HBV/HCV and HIV Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. HIV promotes liver disease by enhancing microbial translocation

HBV/HCV and HIV : 

HBV/HCV and HIV HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the α-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects.

Slide 78: 

The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, AAL, in addition, levels of LPS .   Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

HBV/HCV and HIV : 

HBV/HCV and HIV Moreover, they have also demonstrated that HBV/HCV coinfection is not a stable condition but that it may present with dynamic virologic profiles characterized by wide fluctuations of HBV and HCV viremia levels over time, with both viruses demonstrating alternating phases of active and suppressed replication.

HBV/HCV and HIV : 

HBV/HCV and HIV a wide spectrum of virologic patterns may also occur in HIV-positive patients with HBV/HCV coinfection. Nevertheless, some considerations should be made: *First, in some cases, lack of detection of HBV DNA might be attributable to 3TC, FTC, or TDF use as part of antiretroviral regimens, although . *Second, undetectable levels of HCV RNA might indicate a resolved infection.

HBV/HCV and HIV : 

HBV/HCV and HIV Finally, HBV and HCV viremia levels might reflect only a temporary virologic status, which might change over time. Therefore, a longitudinal evaluation of HBV and HCV should be recommended in HIV-infected patients who are HbsAg- and anti-HCV-positive to assess their current virologic status and tailor the most proper therapeutic approach. JAIDS Journal of Acquired Immune Deficiency Syndrome April 2007 - Volume 44 - Issue 5 - pp 606-607

Still confusing? : 

Thank you Dr MOHAMMED Emam BOSH BEN LADEN or USAMA .W BOSH Still confusing?