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Similaire à HIV, HCV and HBV Coinfection: Epidemiology, Novel Therapies and Management
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HIV, HCV and HBV Coinfection: Epidemiology, Novel Therapies and Management
- 1. HIV, HCV and HBV COINFECTION Dushyantha Jayaweera, M.D., M.R.C.O.G., F.A.C.P. Professor in Clinical Medicine Division of Infectious Diseases University of Miami Miller School of Medicine
- 4. HCV Prevalence by Selected Groups in the United States Hemophilia Injecting Drug Users Surgeons Hemodialysis Average Proportion Anti-HCV Positive (%) General Population Adults Military Personnel STD Clients Pregnant Women Centers for Disease Control and Prevention, 2003. 87 79 10 6 3.5 2 1 0.3 0 10 20 30 40 50 60 70 80 90 100
- 5. Infectious Disease Burden Among Released Inmates: United States 1997 1. Hammett TM, et al. Am J Public Health. 2002;92:1789-1794. 2. McQuillan GM, et al. In: Rizzetto M, et al, editors. Viral hepatitis and liver disease. Turin, Italy: Edizioni Minerva Medica; 1997. p. 267-270. *Data based on prevalence estimate. † Centers for Disease Control and Prevention estimate. Infection/Disease Infected Inmates Released [1] Total Infected in US Population % of Total Infected Population [1] HCV (anti-HCV+) 1,321,781-1,943,796 4,500,000* [2] 29.4-43.2 HIV 150,950–196,555 750,000 † 20.1-26.2 TB 12,531 31,660 † 39.6
- 11. Worldwide Distribution of HCV Genotypes Zein N. Clin Microbiol Rev. 2000;13:223-235. Reproduced with permission. http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999 . 1a 1b 2 3 4 5 6 7-8-9 Others
- 18. Increased Risk of Cirrhosis and ESLD in HIV/HCV Coinfected Patients Graham et al. Clin Infect Dis. 2001;33:562-569. Histological Cirrhosis Decompensated Liver Disease Combined Benhamou Pol Soto Makris Makris Telfer Eyster Lesens Combined 10.83 2.07 1.0 .76 Relative Risk (95% CI) .61 1.0 6.14 10 175.32 CI, confidence interval; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus.
- 19. HIV/HCV Coinfection Trials PEG IFN/RBV PEG IFN alfa-2a 180 µg + RBV 600 mg 1 g/d IFN alfa-2a 6 MIU 3 MIU + RBV 600 mg 1 g/d ACTG 5071 USA (N = 133) PEG IFN alfa-2a 180 µg + RBV 800 mg IFN alfa-2a 3 MIU + RBV 800 mg PEG IFN alfa-2a 180 µg + RBV placebo 800 mg APRICOT International (N = 868) PEG IFN alfa-2b 1.5 μg/kg + RBV 800 mg IFN alfa-2b 3 MIU + RBV 800 mg RIBAVIC France (N = 412) Treatment Regimen Study
- 21. APRICOT Virologic Response*–End of Treatment vs End of Follow-up (Genotype 1) *Defined as <50 IU/mL HCV RNA. Torriani et al. 11 th CROI; February 8-11, 2004; San Francisco, Calif. Abstract 112. 8 21 38 7 14 29 0 10 20 30 40 50 60 Response (%) IFN alfa-2a /RBV PEG IFN alfa-2a / Placebo PEG IFN alfa-2a / RBV EOT EOT SVR SVR SVR EOT
- 22. APRICOT Virologic Response*–End of Treatment vs End of Follow-up (Genotype 2 and 3) *Defined as <50 IU/mL HCV RNA. Torriani et al. 11 th CROI; February 8-11, 2004; San Francisco, Calif. Abstract 112. Response (%) IFN alfa-2a /RBV PEG IFN alfa-2a / Placebo PEG IFN alfa-2a / RBV EOT SVR EOT SVR EOT SVR
- 25. HCV Lifecycle and STAT-C Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release (+) RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen ER lumen LD LD LD NS3/4 protease inhibitors NS5B polymerase inhibitors *Role in HCV lifecycle not well defined NS5A* inhibitors
- 29. On-Treatment Viral Kinetics STAT-C drugs may improve both first and second phase kinetics Second phase First phase HCV RNA 0 12 24 36 48 4 HCV RNA negative in blood Wks
- 30. Resistant Variants occurs Naturally
- 40. Maximize Response and Minimize Resistance
- 44. Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration World Health Organization. Geographic Prevalence of HBsAg. Data from 1996 (unpublished). http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm . Accessed: June 14, 2007 2002 Yearbook of Immigration Statistics. http://uscis.gov/graphics/shared/aboutus/statistics/IMM02yrbk/IMM2002list.htm . Accessed: June 14, 2007. Mahoney FJ. Clin Microbiol Rev . 1999;12:351-366. HBsAg Prevalence 8% - High 2-7% - Intermediate <2% - Low Immigration numbers summed by continent from 1996-2002 ~2 million Asians ~400,000 South Americans ~350,000 Africans ~930, 000 Europeans
- 46. Clinical Liver Disease and HBV Genotype Duong TN, et al. Journal of Medical Virology. 2004;72:551–557. Diagnosis, n (%) Genotypes N Asymptomatic carrier Chronic hepatitis Liver cirrhosis HCC Genotype A 11 8 (72.7) 3 (27.3) 0 0 Genotype B 14 10 (71.4) 3 (21.4) 0 1 (7.2) Genotype C 350 129 (36.8) 126 (36.0) 50 (14.3) 45 (12.9) Genotype D 38 32 (84.2) b 6 (15.8) a 0 0 a a P <0.05 vs genotype C. b P <0.001 vs genotype C.
- 47. Is HBsAg present? Is IgM anti-HBc present? Is HBeAg or HBV DNA present? Is anti-HBs present? Chronic Hepatitis Acute Hepatitis Replicative HBV infection Non-replicative HBV infection Recovered or vaccinated +/- anti-HBc No HBV infection No Yes Yes Yes Yes No No No Anti-HBc +/- no yes
- 50. Management Roadmap According to 24 Week Virologic Response Add another drug without cross resistance Monitor every 3 months Add another drug or Continue Monitor every 3 months Continue Monitor every 6 months Inadequate response >10 4 copies/mL Complete response <300 copies/mL Partial response 300-10 4 copies/mL Week 24: Early predictors of efficacy Keeffe et al. Clin Gastroenterol Hepatol, 2007
- 52. Cross Resistance with HBV Drugs Yang H, et al. Hepatology. 2003;38:705A. Lai CL, et al. Hepatology. 2003;38:262A. V173L L180M A181V A184G S202I M204I M204V N236T M250V Lamivudine Entecavir Telbivudine Emtricitabine Adefovir YMDD
- 57. Thank You Dushyantha Jayaweera, M.D., M.R.C.O.G., F.A.C.P. Professor in Clinical Medicine Division of Infectious Diseases University of Miami Miller School of Medicine
Notes de l'éditeur
- HCV, hepatitis C virus; STDs, sexually transmitted diseases. As mentioned, HCV infection is also commonly found in hemophiliacs who received blood products before 1992. One can see a markedly lower prevalence in the other risk groups shown on this slide, which again emphasizes the high rate of HCV transmission by injection drug use and other blood exposures.
- HCV, hepatitis C virus; TB, tuberculosis. The Centers for Disease Control and Prevention estimated that between 1.3 million and 1.9 million of the estimated 4.5 million individuals infected with HCV in the United States in 1997 were involved in the correctional system. Since there is little reason to suspect that this has changed, these data again underscore the importance of HCV detection in correctional settings.
- Natural History of HCV Infection Key Point: The outcomes of HCV infection and estimates of their frequency are shown in the slide. The majority of patients with acute infection develop chronic hepatitis; however, the severity of chronic liver disease can vary. The most important sequelae of chronic HCV infection include progressive liver fibrosis leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). References 1. Hoofnagle JH. Hepatitis C: the clinical spectrum of disease. Hepatology . 1997;26(suppl 1):15S-20S. 2. National Institutes of Health. NIH consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements . 2002;19(3):1-46.
- Factors Associated with Disease Progression Key Point: Risk factors associated with fibrosis progression are age at infection, estimated duration of infection, alcohol consumption, and male sex.1 An immunocompromised state, occurring secondary to HIV or HBV infection, also increases the risk for progression.2 Fibrosis progression is not associated with viremia, genotype, mode of transmission, or ALT levels. Genotype and high versus low viremia showed no association with fibrosis progression, regardless of age strata.1 References 1. Poynard T, Bedossa P, Opolon P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet . 1997;349:825-832. 2. National Institutes of Health. NIH consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements . 2002;19(3):1-46.
- Extrahepatic Manifestations Associated with HCV Key Point: HCV is frequently reported to complicate extrahepatic manifestations. Among those associated with high degree of certainty to HCV are mixed cryoglobulinemia, noncryoglobulinemic systemic vasculitis, splenic lymphoma, fatigue, porphyria cutanea tarda, sicca syndrome, and autoantibodies production. The mechanisms through which HCV may promote or induce extrahepatic manifestations currently remain unclear and need further investigation. References 1. Sene D, Limal N, Cacoub P. Hepatitis C virus-associated extrahepatic manifestations: a review. Metab Brain Dis . 2004;19(3-4):357-381. 2. National Institutes of Health. NIH consensus statement on management of hepatitis C: 2002. NIH Consens State Sci Statements . 2002;19(3):1-46.
- HCV Testing Algorithm Regarding negative HCV RNA, retesting at 6 months can be considered as “a single positive qualitative assay for HCV RNA confirms active HCV replication, but a single negative assay does not exclude viremia and may reflect only a transient decline in viral level below the level of detection of the assay.” Reference NIH Consensus Conference Statement 2002.
- HCV, hepatitis C virus.
- Histopathological Lesion Evaluation Key Point: The current practice for reporting histopathologic evaluation of chronic hepatitis involves separate statements for the cause of disease, if known, for severity of necroinflammatory lesions, and for the extent of parenchymal fibrosis (stage). Reference Brunt EM. Grading and staging the histopathological lesions of chronic hepatitis: the Knodell histology activity index and beyond. Hepatology . 2000;31(1):241-246.
- Utility of Noninvasive Alternatives to Liver Biopsy Recent studies suggest that due to limitations and risks of biopsy and improvement in diagnostic accuracy of biochemical markers, liver biopsy should no longer be considered mandatory in patients with CHC. FibroTest ActiTest (FT-AT), a panel of biochemical markers, was found to have high diagnostic value for fibrosis (FT range 0.00-1.00) and necroinflammatory histological activity (AT range 0.00-1.00). Neither test, however, can truly distinguish between histologic stages of fibrosis. In addition, a large percentage of patients fall into an indeterminate group when tested. Therefore, the utility of noninvasive surrogate markers of liver fibrosis in replacing liver biopsy is not feasible. Further studies are warranted and due to the disadvantages of liver biopsy (risk of adverse events, sampling error, inter- and intrapathologist variability), other alternatives should continue to be sought. References 1. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol . 2004;3:1-12. 2. Afdhal NH. Diagnosing fibrosis in hepatitis C: is the pendulum swinging from biopsy to blood tests? Hepatology . 2003;37(5):972-974.
- Goals of Therapy Clinically relevant goals for treatment of HCV are classified as primary or secondary. The primary goal is the eradication of the virus as evidenced by negative HCV RNA. The secondary goals include the histologic improvement of hepatic inflammation and fibrosis as evidenced by delayed fibrosis and progression to cirrhosis and prevention of hepatic decompensation and HCC. Reference Lindsay KL. Introduction to therapy of hepatitis C. Hepatology . 2002;36:S114-S120.
- Predictors of Virologic Response Efficacy of therapy is dependent on viral factors and host factors. Genotype and viral load have shown to impact the sustained virologic response of pegylated interferons. Host factors including age, cirrhosis, race, gender, and weight have also been shown to be predictors of response. References 1. Ferenci. Predictors of response to therapy for chronic hepatitis C. Semin Liver Dis . 2004;24(suppl 2):25-31. 1. Lindsay KL. Introduction to therapy of hepatitis C. Hepatology . 2002;36: S114-S120.
- BACKGROUND : Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with HCV. However, there is little quantitative information about the long-term effects of HCV infection on mortality. METHODS: A cohort study evaluated the effect of liver cancer and liver disease on mortality in 4865 haemophilic men and boys in the UK. Patients were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and followed up from first recorded exposure to Jan 1, 1993. FINDINGS: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer . For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older, prospectively. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men over 45 years old. INTERPRETATION: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals infected with hepatitis C and that risk increases further with concomitant HIV-1. REFERENCE: Darby SC, Ewart DW, Giangrande PL, et al. Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation. Lancet . 1997;350:1425-1431.
- The results from 3 studies evaluating the safety and efficacy of PEG IFN/RBV combination therapy in the HIV/HCV coinfected patient were released at this year’s CROI meeting. The French RIBAVIC trial studied PEG IFN alfa-2b/RBV while both the ACTG and APRICOT trials studied the safety and efficacy of PEG IFN alfa-2a/RBV and were conducted in the United States.
- HCV, hepatitis C virus; ER, endoplasmic reticulum; LD, luminal domain; STAT-C, specifically targeted antiviral therapy for HCV. The HCV lifecycle and the mechanism of actions of various STAT‑C agents are shown on this slide. The virus binds to specific cell surface receptors, is endocytosed, fuses with the hepatocyte membrane, and becomes uncoated before creating a replication membranous web where the virus is replicated, proteins are translated, new variants are assembled and are transported again to the membrane and released into the circulation. The NS3/4a protease inhibitors’ mechanisms of action are to inhibit the cleavage of the viral polyprotein into various independent HCV proteins. NS5B polymerase inhibitors interfere with the RNA replication process of the virus, and there is an interesting new molecule class, the NS5A inhibitors, that probably interfere with various stages of creation of this membranous replication web, but their role has not been well defined in the HCV lifecycle.
- HCV, hepatitis C virus; STAT-C, specifically targeted antiviral therapy for HCV. Therefore, data strongly support the fact that despite shortening therapy, SVR rates can be improved through the use of STAT-C agents. This is widely interpreted to indicate that the STAT-C molecules are affecting the first-phase virologic decay and potentially the second-phase virologic decay, as shown in this figure; however, these hypotheses will require confirmation.
- Geographic Prevalence of Chronic Hepatitis B May Be Impacted by Migration The frequency of HBV infection and patterns of HBV transmission vary dramatically in different parts of the world. Approximately 45% of the world’s population live in areas where the prevalence of chronic HBV infection is high (>8% of the population is HBsAg positive), 43% live in areas of intermediate prevalence (2% to 7% of the population is HBsAg positive), and only 12% of the world’s population live in areas of low endemicity (<2% of the population is HBsAg positive). In areas of high endemicity, the lifetime risk of HBV infection is >60%. Such areas include most of Asia (except Japan and India), most of the Middle East, the Amazon Basin of South America, most Pacific Island Groups, Africa, and other special populations, such as Native Alaskans, Australian Aborigines, and Maoris in New Zealand. Most infections occur at birth or during early childhood when the risk of acquiring chronic infection is the greatest. There is little recognition of acute disease, as most early childhood HBV infections are asymptomatic. However, the rates of chronic liver disease and liver cancer are high. In areas of intermediate endemicity, the lifetime risk of HBV infection is 20% to 60% and infections occur in all age groups. Acute disease is commonly recognized as many infections occur in adolescents and young adults. Additionally, high rates of HBV-related chronic liver disease occur due to the high prevalence of chronic HBV infection. In areas of low endemicity, the lifetime risk of infection is <20% and most infections occur among adults in well-defined risk groups. In the United States, prevalence of HBsAg may be impacted by migratory trends from regions of high endemicity. From 1996 (when the data were gathered for the HBsAg prevalence) to 2002, approximately 1.9 million, 933,000, 337,000, and 401,000 persons have immigrated from Asia, Europe, Africa, and South America, respectively. References World Health Organization. Geographic Prevalence of HBsAg. http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed: September 13, 2004. 2002 Yearbook of Immigration Statistics. http://uscis.gov/graphics/shared/aboutus/statistics/IMM02yrbk/IMM2002list.htm. Accessed: September 22, 2004. Mahoney FJ. Clin Microbiol Rev . 1999;12:351-366.
- Natural History of HBV: Development of HBeAg-negative disease There are two distinct types of HBV: wild-type and variant HBV. HBV variants or subtypes (core or pre-core mutants) can arise during the course of chronic HBV infection as a result of a mutation/variation in the core/pre-core gene of wild-type HBV. The variants lose their ability to secrete ‘HBe’ antigen (HBeAg). Once HBeAg-negative virus becomes the predominant subtype, the patient is defined as having the HBeAg-negative form of CHB. Reference: 1. Hadziyannis, Vassilopoulos. Hepatology 2001.