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Disclosure of Financial Relationships This speaker has the following significant financial relationships with commercial entities to disclose:. Speaker ? Tibotec, Merck, BIPI, Gilead, BMSResearch Support ? ViiV, Tobira Pharmaceuticals, Vertex, PfizerConsultant ? ViiV, Tibotec, Gilead. This slide
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1. HIV and Hepatitis C
Co-Infection
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
2. Disclosure of Financial RelationshipsThis speaker has the following significant financial relationships with commercial entities to disclose: Speaker – Tibotec, Merck, BIPI, Gilead, BMS
Research Support – ViiV, Tobira Pharmaceuticals, Vertex, Pfizer
Consultant – ViiV, Tibotec, Gilead
3. Case Study 45 year old HIV and HCV infected lady from Puerto Rico comes to the clinic and her HIV VL is <50 copies/ml and the CD4 cell count is 780cell/mm. She is asymptomatic. However, on examination, she has liver enlargement 14cm , spleen 4 CM below the costal margin and mild ascites. The labs showed Albumin 2.8, INR 2.0, T bili 0.3, AST of 123 and ALT of 119. She says she doe not feel well. Her Child Pugh Score is 7 and the MELD score is 10.
5. Worldwide Prevalence: % of HIV Patients Who Are Coinfected With HCV
In the US, it is estimated that 30% of the HIV-infected living individuals are coinfected with HCV. Similar rates (33%) have been estimated for Western Europe, although the number of HIV-infected individuals is less well defined. The magnitude of the problem is alarming in countries such as Spain, where at least half of the 130,000 HIV-infected patients are estimated to be HIV/HCV coinfected. In fact, among some subgroups of HIV-infected patients, such as IVDU, the prevalence of HCV coinfection is as high as 70-90%.
References
Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813-826.
Chanbancherd P, Paris RM, Torugsa K, et al. High frequency of HIV-1 and hepatitis C co-infection among young Thai men: evidence for a changing pattern of HIV transmission in Thailand. Southeast Asian J Trop Med Public Health. 2003;Sept;34:580-582.Worldwide Prevalence: % of HIV Patients Who Are Coinfected With HCV
In the US, it is estimated that 30% of the HIV-infected living individuals are coinfected with HCV. Similar rates (33%) have been estimated for Western Europe, although the number of HIV-infected individuals is less well defined. The magnitude of the problem is alarming in countries such as Spain, where at least half of the 130,000 HIV-infected patients are estimated to be HIV/HCV coinfected. In fact, among some subgroups of HIV-infected patients, such as IVDU, the prevalence of HCV coinfection is as high as 70-90%.
References
Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813-826.
Chanbancherd P, Paris RM, Torugsa K, et al. High frequency of HIV-1 and hepatitis C co-infection among young Thai men: evidence for a changing pattern of HIV transmission in Thailand. Southeast Asian J Trop Med Public Health. 2003;Sept;34:580-582.
6. Transmission Sources Before 1990, an estimated 10% of blood transfusions resulted in HCV infection. Since blood screening for HCV, intravenous drug use has become the leading cause of transmission in the Western world (CDC FAQ).
Before 1990, an estimated 10% of blood transfusions resulted in HCV infection. Since blood screening for HCV, intravenous drug use has become the leading cause of transmission in the Western world (CDC FAQ).
7. Causes of Liver Diseasein HIV Infection Slide: Causes of Liver Disease in HIV Infection
There are multiple causes of liver disease in patients with HIV infection.
These include:
Immune reconstitution syndrome.
Coinfection with hepatitis B (HBV), C (HCV), and/or A (HAV).
Emergence of opportunistic infections
Alcohol abuse or injection drug use.
Antiretroviral agents directly and indirectly via secondary diabetes and dyslipidemia which may contribute to fatty liver disease.
Slide: Causes of Liver Disease in HIV Infection
There are multiple causes of liver disease in patients with HIV infection.
These include:
Immune reconstitution syndrome.
Coinfection with hepatitis B (HBV), C (HCV), and/or A (HAV).
Emergence of opportunistic infections
Alcohol abuse or injection drug use.
Antiretroviral agents directly and indirectly via secondary diabetes and dyslipidemia which may contribute to fatty liver disease.
8. HCV Lifecycle 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; 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.
9. 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.”
ReferenceNIH Consensus Conference Statement 2002.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.”
ReferenceNIH Consensus Conference Statement 2002.
10. 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.
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.
11. 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.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.
12. 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.
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.
13. 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.
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.
14. Independent Predictorsof Liver-Related Death Slide: Independent Predictors of Liver-Related Death
Predictors of liver-related deaths were:1
Latest CD4 cell count (adjusted relative rate [RR] 16.06).
Age (RR 1.3 [data not shown]).
Intravenous drug use (RR 2.0).
HCV infection (RR 6.7).
Active HBV infection (RR 3.7).
Reference
Weber R, Sabin CA, Friis-Mřller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632-1641.
Slide: Independent Predictors of Liver-Related Death
Predictors of liver-related deaths were:1
Latest CD4 cell count (adjusted relative rate [RR] 16.06).
Age (RR 1.3 [data not shown]).
Intravenous drug use (RR 2.0).
HCV infection (RR 6.7).
Active HBV infection (RR 3.7).
Reference
Weber R, Sabin CA, Friis-Mřller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med. 2006;166:1632-1641.
15. HIV Coinfection Increases the Riskof Cirrhosis and ESLD Due to HCV Slide: HIV Coinfection Increases the Risk of Cirrhosis and ESLD Due to HCV
The meta-analysis conducted by Graham and colleagues provides a comprehensive summary of the studies showing that HIV infection accelerates the course of HCV infection.1
Eight studies included outcomes of histologic cirrhosis or decompensated liver disease.
Patients with HIV/HCV coinfection were at an increased risk of:1
Cirrhosis (RR: 2.07; 95% CI 1.40-3.07).
Decompensated liver disease (RR: 6.14; 95% CI 2.86-13.20).
Reference
Graham CS, Baden LR,Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-569.
Slide: HIV Coinfection Increases the Risk of Cirrhosis and ESLD Due to HCV
The meta-analysis conducted by Graham and colleagues provides a comprehensive summary of the studies showing that HIV infection accelerates the course of HCV infection.1
Eight studies included outcomes of histologic cirrhosis or decompensated liver disease.
Patients with HIV/HCV coinfection were at an increased risk of:1
Cirrhosis (RR: 2.07; 95% CI 1.40-3.07).
Decompensated liver disease (RR: 6.14; 95% CI 2.86-13.20).
Reference
Graham CS, Baden LR,Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562-569.
16. Impact of HIV on InfectionWith Hepatitis Viruses HIV/HCV coinfection
Increased HCV-RNA titers
Lower response to HCV treatment
More rapid progression to cirrhosis, ESLD, and death Slide: Impact of HIV on Infection With Hepatitis Viruses
HIV/HCV coinfection is associated with increased HCV-RNA titers, lower response to HCV treatment, and more rapid progression to cirrhosis, end-stage liver disease (ESLD), and death.
HIV/HBV coinfection is associated with a higher risk of chronic carrier state, lower rate of spontaneous loss of HBeAg/HBsAg, lower seroconversion to anti-HBe/anti-HBs, higher rate of viral reactivation and HBV replication, and a higher rate of occult HBV.Slide: Impact of HIV on Infection With Hepatitis Viruses
HIV/HCV coinfection is associated with increased HCV-RNA titers, lower response to HCV treatment, and more rapid progression to cirrhosis, end-stage liver disease (ESLD), and death.
HIV/HBV coinfection is associated with a higher risk of chronic carrier state, lower rate of spontaneous loss of HBeAg/HBsAg, lower seroconversion to anti-HBe/anti-HBs, higher rate of viral reactivation and HBV replication, and a higher rate of occult HBV.
17. Benefits of HAART inHIV/HCV-Coinfected Patients Controls HIV and improves immune status
May slow HCV-related liver disease progression
Overall mortality
Liver-specific mortality Slide: Benefits of HAART in HIV/HCV-Coinfected Patients
In patients with HIV/HCV coinfection, the benefits of HAART include:
Control HIV replication and improve immune status.
May slow HCV-related liver disease progression with regard to overall and liver-specific mortality.Slide: Benefits of HAART in HIV/HCV-Coinfected Patients
In patients with HIV/HCV coinfection, the benefits of HAART include:
Control HIV replication and improve immune status.
May slow HCV-related liver disease progression with regard to overall and liver-specific mortality.
18. Indications for HCV treatment Patient willing and motivated to treat their HCV infection
Acute HCV infection
A biopsy showing chronic hepatitis with significant fibrosis (greater than portal fibrosis)
Cryoglobulinemic vasculitis, membranoproliferative glomerulonephritis
Compensated liver disease and acceptable hematologic parameters
19. Absolute Contraindications for HCV Therapy Uncontrolled active major psychiatric illness
Hepatic decompensation (hepatic encephalopathy, coagulopathy, or ascites)
Known allergy to interferon and/or ribavirin
Severe poorly controlled co morbidities – DM, cardiac failure, CAD, HTN, COPD, active cancer, untreated thyroid disease, SLE, CRF
Patients concurrently receiving didanosine
Women pregnant, nursing, child-bearing potential and can not practice contraception
20. Baseline Laboratory Studies Prior to Starting Therapy CBC, CMP, TSH, HCV RNA quantitative level, CD4 cell count, HIV RNA
All women of childbearing potential require a negative pregnancy test immediately
Counseling Regarding Avoiding Pregnancy
Eye and psychatric evaluation
In patients over 50 years cardiac evaluation which may need include a stress test depending on the risk factors
Liver pathology? Bx or no Bx
21. 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.
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.
22. HCV FibroSURE™ (FibroTest/ActiTest) A noninvasive blood test that combines the quantitative results of six serum biochemical markers, a2-macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, ?-glutamyl transpeptidase (GGT), and ALT, with a patient’s age and gender in a patented artificial intelligence algorithm to generate a measure of fibrosis and necroinflammatory activity in the liver.
23. FibroSure can be Used for Assessment of liver status following a diagnosis of HCV
Baseline determination of liver status before initiating HCV therapy
Post treatment assessment of liver status six months after completion of therapy
Noninvasive assessment of liver status in patients who are at increased risk of complications from a liver biopsy
24. HCV FibroSURE™NOT Recommended Interferon/ribavirin therapy, since ribavirin may in duce hemolysis, low haptoglobin levels, and falsely elevated fibrosis
Gilbert disease, acute hemolysis, acute viral hepatitis, drug-induced hepatitis, genetic liver disease, autoimmune hepatitis, and/or extrahepatic cholestasis.
25. FibroScan
27. HIV/HCV Coinfection:Goals of Therapy Achieve a sustained virologic response
Undetectable HCV RNA level 6 months after the end of treatment
Viral eradication (ie, cure)
Reduce liver disease
Fibrosis and necroinflammation
Decrease the risk of hepatotoxicity associated with antiretroviral therapy Slide: HIV/HCV Coinfection: Goals of Therapy
The goals of therapy in patients with HIV/HCV coinfection are to achieve a sustained virologic response (ie, undetectable HCV RNA level 6 months after the end of treatment, viral eradication [ie, cure]), reduce liver disease (ie, fibrosis and necroinflammation), and decrease the risk of hepatotoxicity associated with antiretroviral therapy.Slide: HIV/HCV Coinfection: Goals of Therapy
The goals of therapy in patients with HIV/HCV coinfection are to achieve a sustained virologic response (ie, undetectable HCV RNA level 6 months after the end of treatment, viral eradication [ie, cure]), reduce liver disease (ie, fibrosis and necroinflammation), and decrease the risk of hepatotoxicity associated with antiretroviral therapy.
29. What is true among the statements given below? The early viral response is when the HCV VL is undetectable at 16 weeks
Ribarvirin is not cleared via the kidneys
15% of HCV infection will spontaneously resolve
Sustained viral response in HCV treatment is when you have stopped HCV treatment and 12 months later the HCV VL is undetectable
30. HIV/HCV Coinfection:What HIV Treatment? Protease Inhibitors
Darunavir - no change in the dose. Severe impairment avoid use
Atazanavir – CPT class B 300mg/day with food, CPT class C contraindicated
Lopinavir – use with caution
Fosamprenavir – CPT 5-6 – 700MG BID with norvir 100mg/day, CPT score 7-8- 700mg BID OR 450 mg BID with norvir 100mg/day, CPT 10 -12 300OR 350 BID with norvir 100mg/day
Slide: HIV/HCV Coinfection: What to Treat With
The treatment of choice for HCV disease is peginterferon + ribavirin.
Peginterferon 2 alfa: 180 µg subcutaneous injection weekly.
Peginterferon 2b: 1.5 µg/kg subcutaneous injection weekly.
It is now recommended to administer ribavirin at a starting dose that is adapted to the body weight of the patient (1000 mg/day for body weight <75 kg and 1200 mg/day for body weight >75 kg).
With regard to NRTIs:
Didanosine is contraindicated because of the risk of mitochondrial toxicity.
It is recommended to avoid stavudine (mitochondrial toxicity and zidovudine (anemia) if possible.
Limited data suggest lower SVR rates with abacavir use.
If an early virologic response (>2 log10 reduction or undetectable HCV RNA) is not achieved at week 12, treatment should be stopped.
Slide: HIV/HCV Coinfection: What to Treat With
The treatment of choice for HCV disease is peginterferon + ribavirin.
Peginterferon 2 alfa: 180 µg subcutaneous injection weekly.
Peginterferon 2b: 1.5 µg/kg subcutaneous injection weekly.
It is now recommended to administer ribavirin at a starting dose that is adapted to the body weight of the patient (1000 mg/day for body weight <75 kg and 1200 mg/day for body weight >75 kg).
With regard to NRTIs:
Didanosine is contraindicated because of the risk of mitochondrial toxicity.
It is recommended to avoid stavudine (mitochondrial toxicity and zidovudine (anemia) if possible.
Limited data suggest lower SVR rates with abacavir use.
If an early virologic response (>2 log10 reduction or undetectable HCV RNA) is not achieved at week 12, treatment should be stopped.
31. HIV/HCV Coinfection:What to use for HCV Treatment? Treatment of choice is peginterferon + ribavirin
Peginterferon dose
2a (180 µg) or 2b (1.5 µg/kg) subcutaneous injection weekly
Ribavirin
Initial weight-adapted dose
<75 kg: 1000 mg/day
>75 kg: 1200 mg/day
Didanosine is contraindicated (mitochondrial toxicity)
Avoid stavudine (mitochondrial toxicity) and zidovudine (anemia) if possible
Limited data suggest lower SVR rates with abacavir use
If an early virologic response (>2 log10 reduction or undetectable HCV RNA) is not achieved at week 12, treatment should be stopped Slide: HIV/HCV Coinfection: What to Treat With
The treatment of choice for HCV disease is peginterferon + ribavirin.
Peginterferon 2 alfa: 180 µg subcutaneous injection weekly.
Peginterferon 2b: 1.5 µg/kg subcutaneous injection weekly.
It is now recommended to administer ribavirin at a starting dose that is adapted to the body weight of the patient (1000 mg/day for body weight <75 kg and 1200 mg/day for body weight >75 kg).
With regard to NRTIs:
Didanosine is contraindicated because of the risk of mitochondrial toxicity.
It is recommended to avoid stavudine (mitochondrial toxicity and zidovudine (anemia) if possible.
Limited data suggest lower SVR rates with abacavir use.
If an early virologic response (>2 log10 reduction or undetectable HCV RNA) is not achieved at week 12, treatment should be stopped.
Slide: HIV/HCV Coinfection: What to Treat With
The treatment of choice for HCV disease is peginterferon + ribavirin.
Peginterferon 2 alfa: 180 µg subcutaneous injection weekly.
Peginterferon 2b: 1.5 µg/kg subcutaneous injection weekly.
It is now recommended to administer ribavirin at a starting dose that is adapted to the body weight of the patient (1000 mg/day for body weight <75 kg and 1200 mg/day for body weight >75 kg).
With regard to NRTIs:
Didanosine is contraindicated because of the risk of mitochondrial toxicity.
It is recommended to avoid stavudine (mitochondrial toxicity and zidovudine (anemia) if possible.
Limited data suggest lower SVR rates with abacavir use.
If an early virologic response (>2 log10 reduction or undetectable HCV RNA) is not achieved at week 12, treatment should be stopped.
32. Summary of Sustained Virologic Response in HIV/HCV-Coinfected Patients Slide: Summary of Sustained Virologic Response in HIV/HCV-Coinfected Patients
Results from the 3 major trials consistently demonstrated that 48-weeks of peginterferon + ribavirin produced substantially higher sustained virologic responses at week 72 compared with interferon + ribavirin.1-3
Patients with genotype 1 are more difficult to treat.
Overall responses are lower in HIV/HCV-coinfected patients compared with historical results in HCV-monoinfected patients.
References
Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451-459.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438-450.
Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.
Slide: Summary of Sustained Virologic Response in HIV/HCV-Coinfected Patients
Results from the 3 major trials consistently demonstrated that 48-weeks of peginterferon + ribavirin produced substantially higher sustained virologic responses at week 72 compared with interferon + ribavirin.1-3
Patients with genotype 1 are more difficult to treat.
Overall responses are lower in HIV/HCV-coinfected patients compared with historical results in HCV-monoinfected patients.
References
Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451-459.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004;351:438-450.
Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.
33. PRESCO Trial: Weight-Based Ribavirin Dosing in HIV/HCV-Coinfected Patients Prospective, open-label study
Spain only
Not randomized or controlled
All CD4 >300 cells/mm3
No didanosine
Weight-based ribavirin
<75 kg: 1000 mg/day
>75 kg: 1200 mg/day
Independent predictors of SVR
HCV genotype 2/3
Lower baseline HCV RNA level
Negative HCV RNA level at week 12
Anemia reasonable Slide: PRESCO Trial: Weight-Based Ribavirin Dosing in HIV/HCV-Coinfected Patients
Nunez and colleagues conducted a prospective, open-label trial evaluating the role of weight-based ribavirin dosing plus peginterferon in 389 HIV/HCV-coinfected patients.1
Study was conducted in centers across Spain and all patients had CD4 >300 cells/mm3.
The study population of the current study included a greater proportion of patients with HCV genotypes 2/3 than did the APRICOT study.
Didanosine was not allowed.
Weight-based ribavirin:
<75 kg: 1000 mg/day.
>75 kg: 1200 mg/day.
Independent predictors of SVR included HCV genotype 2/3, lower baseline HCV RNA level, and negative HCV RNA level at week 12.1
The incidence of any grade of anemia was 42% (162/389), with only 1.5% of patients requiring treatment discontinuation due to anemia.1
These results add to the existing evidence that emphasize that optimal ribavirin exposure can be given safely and is critical to maximizing SVR and minimizing the incidence of relapses after treatment discontinuations.1
Reference
Nunez M, Miralles C, Berdún MA, et al. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial. AIDS Res Hum Retroviruses. 2007;23:972-982.
Slide: PRESCO Trial: Weight-Based Ribavirin Dosing in HIV/HCV-Coinfected Patients
Nunez and colleagues conducted a prospective, open-label trial evaluating the role of weight-based ribavirin dosing plus peginterferon in 389 HIV/HCV-coinfected patients.1
Study was conducted in centers across Spain and all patients had CD4 >300 cells/mm3.
The study population of the current study included a greater proportion of patients with HCV genotypes 2/3 than did the APRICOT study.
Didanosine was not allowed.
Weight-based ribavirin:
<75 kg: 1000 mg/day.
>75 kg: 1200 mg/day.
Independent predictors of SVR included HCV genotype 2/3, lower baseline HCV RNA level, and negative HCV RNA level at week 12.1
The incidence of any grade of anemia was 42% (162/389), with only 1.5% of patients requiring treatment discontinuation due to anemia.1
These results add to the existing evidence that emphasize that optimal ribavirin exposure can be given safely and is critical to maximizing SVR and minimizing the incidence of relapses after treatment discontinuations.1
Reference
Nunez M, Miralles C, Berdún MA, et al. Role of weight-based ribavirin dosing and extended duration of therapy in chronic hepatitis C in HIV-infected patients: the PRESCO trial. AIDS Res Hum Retroviruses. 2007;23:972-982.
34. Common Adverse Effects with HCV Therapy The most common: influenza-like symptoms (fever, headache, myalgia), fatigue, rash, and neuropsychiatric effects (depression, irritability, insomnia, and cognitive dysfunction).
Peginterferon can induce an autoimmune thryoiditis resulting in hyperthyroidism or hypothyroidism.
Peginterferon plus ribavirin is associated with nausea, vomiting, weight loss cytopenias (anemia, neutropenia, lymphopenia and thrombocytopenia)
35. HCV Lifecycle and STAT-C Targets 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; 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.
37. New HCV Agents – Boceprevir and Telaprevir Boceprevir and Telaprevir, the 2 new oral HCV protease inhibitors has phase 3 data
Telaprevir (plus peg/rbv) 75% of patients achieved SVR. Telaprevir is taken only for 12 weeks, peg/RBV is taken during the entire 48 weeks
In mono infection with HCV 68% of patients in studies had undetectable HCV viral load at 4 weeks and 58% at weeks 4 and 12 (212/363).
38. New HCV Agent- Telaprevir Relapse rates were low, 9%. On-treatment virologic failure rates were only 3%. Patients with no, mild or portal fibrosis had a 78% SVR. Patients with cirrhosis with a 62% SVR, and for African Am. the SVR was 62%
Rash 56% with 6% a severe rash, on average hemoglobin went down from 12.3 g/dL approx to 11 by week 8.
It is expected that FDA will approve this month
39. Pharmacokinetic Interactions Between ARVs and Telaprevir Background: Atazanavir/ritonavir (ATV/r), darunavir/r (DRV/r), fosamprenavir/r (FPV/r), and lopinavir/r (LPV/r) are substrates and inhibitors of CYP3A. Efavirenz (EFV) is an inducer of CYP3A. Telaprevir (TVR) is a substrate and inhibitor of CYP3A. In previous trials with TVR 750 mg every 8 hours, TVR Cmin was reduced by 47% by EFV and tenofovir AUC24h was increased by 30% by TVR. Interactions between TVR and antiretroviral (ARV) agents were evaluated to guide studies of TVR in HIV/hepatitis C virus (HCV) co-infected patients.
Methods: Three separate open-label, randomized cross-over trials were conducted in HIV/HCV– healthy volunteers. In 2 studies, volunteers received 2 treatments; TVR 750 mg every 8 hours for 10 days, followed by a washout and ATV/r 300/100 mg once daily, DRV/r 600/100 mg twice daily, FPV/r 700/100 mg twice daily, or LPV/r 400/100 mg twice daily (n = 20 each) for 20 days with co-administration of TVR 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. In another study, 20 volunteers started TVR 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received TVR 1125 mg every 8 hours and EFV/TDF 600/300 mg once daily for 7 days or TVR 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout. TVR was taken with food and EFV/TDF was taken on an empty stomach in the morning. Least square means (LSMeans) and 90%CI of treatment ratios (test/reference) were calculated for the log-transformed AUCtau and Cmin
Background: Atazanavir/ritonavir (ATV/r), darunavir/r (DRV/r), fosamprenavir/r (FPV/r), and lopinavir/r (LPV/r) are substrates and inhibitors of CYP3A. Efavirenz (EFV) is an inducer of CYP3A. Telaprevir (TVR) is a substrate and inhibitor of CYP3A. In previous trials with TVR 750 mg every 8 hours, TVR Cmin was reduced by 47% by EFV and tenofovir AUC24h was increased by 30% by TVR. Interactions between TVR and antiretroviral (ARV) agents were evaluated to guide studies of TVR in HIV/hepatitis C virus (HCV) co-infected patients.
Methods: Three separate open-label, randomized cross-over trials were conducted in HIV/HCV– healthy volunteers. In 2 studies, volunteers received 2 treatments; TVR 750 mg every 8 hours for 10 days, followed by a washout and ATV/r 300/100 mg once daily, DRV/r 600/100 mg twice daily, FPV/r 700/100 mg twice daily, or LPV/r 400/100 mg twice daily (n = 20 each) for 20 days with co-administration of TVR 750 mg every 8 hours from day 11 onwards, or vice versa. All compounds were taken with food. In another study, 20 volunteers started TVR 750 mg every 8 hours for 7 days followed by EFV/tenofovir disoproxil fumarate (TDF) 600/300 mg once daily for 7 days after a washout. Subsequently, volunteers received TVR 1125 mg every 8 hours and EFV/TDF 600/300 mg once daily for 7 days or TVR 1500 mg every 12 hours and EFV/TDF 600/300 mg once daily for 7 days in a randomized order without a washout. TVR was taken with food and EFV/TDF was taken on an empty stomach in the morning. Least square means (LSMeans) and 90%CI of treatment ratios (test/reference) were calculated for the log-transformed AUCtau and Cmin
40. New HCV Agents - Boceprevir Patients received a 4-week lead in with peg/rbv before starting boceprevir, hence, this will likely be used this way.
Patients with a 1 log or more decline in viral load after the 4-week lead-in, 82% achieved SVR. Patients with undetectable viral load at week 8, 90% achieved SVR.
49% had anemia, 1% discontinued, 13% dose reduced due to anemia, 24% used EPO for treatment of anemia.
41. New HCV Agents - Boceprevir RESPOND 2 study - The SVR were significantly higher in patients randomized to receive boceprevir (56-75%) compared to those who got peginterferon alfa-2b plus ribavirin alone (40 %).
Week 4 lead-in response predicted SVR: if a patient had 1 log or more decline in viral load at week 4, 73-79% achieved SVR.
The boceprevir treatment arm was associated with an incremental risk of significant anemia compared to peginterferon/ribavirin and epoetin alfa was more frequently used.
42. New Information Lambda Interferon less side effects
Genotype 1a vs 1b appears to matter: 1a appears to respond less well to protease inhibitors than genotype 1b because drug resistance appears more likely to emerge with 1a
Therapeutic approaches that will likely be more effective for 1a include more potency, nucleosides like R7128 and nucleotides like PSI7977 and PSI938 as they don't develop resistance easily.
49. What is true among the statements given below? HCV Genotype one has a poor response to treatment
HCV Genotype one has more rapid progression to cirrhosis
Genotype IL 28 B TT genotype will respond well to interferon
In HCV/HIV coinfection, the dose of ribarvirin has no relationship to treatment response
50. Outcomes of Liver Transplantation in HCV-HIV Co-Infected Recipients This prospective U.S. multicenter cohort study compared patient and graft survival in 89 HCV-HIV co-infected versus 235 HCV mono-infected.
The study is completed and data is being analyzed.
Our own experience has been that this is not a benign procedure and it carries it’s mortality and morbidity.
This study was supported by the Solid Organ Transplantation in HIV: Multi-Site Study (AI052748) funded by the National Institute of Allergy and Infectious Diseases, the University of California University-wide AIDS Research Program (TP00-SF-154 and TP99-SF-001), and UCSF Liver Center Grant P30 DK-26743
51. Graft Survival: HCV
52. Time to First Acute Rejection
53. Drug Interactions One of the most challenging problems in HIV transplant is the interaction between prograf and the HIV medications.
Drugs with no interactions – all NRTIs, integrase inhibitor such as raltegravir (Isentress)
AZT Zidovudine (retrovir)
3TC Lamivudine (Epivir) and FTC Emtricitabine (Emtriva)
Tenofovir (Viread)
Abacavir (Ziagen)
54. Drug Interactions Drugs which increase the prograf levels – all boosted PI s that block P450 CYP 3 A enzyme system
Darunavir with ritonavir
Atazanavir with ritonavir
Lopinavir with ritonavir
Fosamprenavir with ritonavir
Saquinavir with ritonavir
55. Drug Interactions Drugs which decrease the prograf levels – all NNRTIs
Efavirenz or EFV/FTC/TDF (Atripla®) both will decrease the level hence you need a higher dose daily
Nevirapine decrease the level slightly but this drug is not used very often in HCV infection.
Drugs which will cause renal damage – Viread and any combination with i.e. EFV/FTC/TDF (Atripla®)
Drugs that do not work with proton pump blockers – Atazanavir
56. Case Study 45 year old HIV and HCV infected lady from Puerto Rico comes to the clinic and her HIV VL is <50 copies/ml and the CD4 cell count is 780cell/mm. She is asymptomatic. However, on examination, she has liver enlargement 14cm , spleen 4 CM below the costal margin and mild ascites. The labs showed Albumin 2.8, INR 2.0, T bili 0.3, AST of 123 and ALT of 119. She says she doe not feel well. Her Child Pugh Score is 7 and the MELD score is 10.
57. What would you do as the health care provider in this case? Ask for an urgent liver transplant
Treat HCV but you do not need a biopsy as she wants to be treated
Ref for transplant evaluations but manage conservatively as the patient is stable and has a low MELD score
58. Take Home Points 200M infected with HCV world wide and US 3-4M
Most patients with HCV/HIV may be treated
The predictors of response include- GT 2-3, low viral load, women, younger age, cirrhosis, whites, low BMI, IL28B – CC genotype
Predictors of disease progression: alcohol, HCV at older age, HIV/HBV, immuno-suppression
Peg interferon/ribarvirin approved, Telaprevir/ Boceprevir not approved for co infection yet
Liver transplant does carry significant mortality and mobidity
59. Thank you